Interstate 99 (I-99) is an Interstate Highway in the United States with two segments: one located in central Pennsylvania and the other in northern Pennsylvania into southern New York along US 15. The southern terminus of the route is near exit 146 of the Pennsylvania Turnpike (I-70/I-76) north of Bedford, where the road continues south as U.S. Route 220 (US 220). The northern terminus of the Pennsylvania segment is at an at-grade intersection with Musser Lane near I-80 near Bellefonte. The northern segment is entirely concurrent with US 15, beginning at I-180 in Williamsport northward into New York to an interchange with I-86 in Corning. Within Pennsylvania, I-99 passes through Altoona and State College—the latter home to the Pennsylvania State University—and is entirely concurrent with US 220.

In November 2024, the northern segment was extended down US 15 to I-180 in Williamsport, entirely concurrent with US 15. Long-term plans call for the two segments of I-99 to be connected using portions of I-80 and US 220 through Pennsylvania. The only current progress on the connection is the direct access interchange at I-80.

Unlike most interstate highway numbers, which were assigned by the American Association of State Highway and Transportation Officials (AASHTO) to fit into a grid, I-99's number was written into Section 332 of the National Highway System Designation Act of 1995 by Bud Shuster, then-chair of the US House Committee on Transportation and Infrastructure, the bill's sponsor, and the representative of the district through which the highway runs. I-99 breaks the AASHTO numbering pattern associated with interstate highways, as it would be expected to lie east of I-97 but instead lies east of I-79 and west of I-81.

I-99 begins at an indirect interchange with US 220 and the Pennsylvania Turnpike (I-70/I-76) north of Bedford. It begins concurrent with US 220, which continues south from the interchange toward the Maryland state line as a two-lane highway known as the Appalachian Thruway. To access the turnpike, drivers are required to use a short segment of US 220 Business (US 220 Bus.). North of the turnpike junction, the freeway becomes the Bud Shuster Highway as it heads through a rural portion of Bedford County. It connects to Pennsylvania Route 56 (PA 56) just west of Bedford County Airport at exit 3 and PA 869 at exit 7 before crossing into Blair County. Here, it meets PA 164 north of East Freedom at exit 23 prior to entering the Altoona area.

In Hollidaysburg, a borough south of the city, I-99 and US 220 connect to US 22 at exit 28, a large modified trumpet interchange. This junction allows travelers to head west toward Ebensburg, Johnstown, and Pittsburgh. The freeway continues to Altoona itself, where it indirectly connects to PA 36 via exit 32. Unlike the original routing of US 220 which goes through the city center, I-99 and US 220 mostly bypass it to the east, connecting to the city via streets leading eastward from the downtown district. At the northern edge of Altoona, PA 764 joins the old alignment of US 220 and parallels I-99 north for three miles (4.8 km) toward Bellwood. PA 764 leaves old US 220 about two miles (3.2 km) south of Bellwood, however, and terminates at I-99 exit 39. Bellwood itself is served by exit 41, which leads to PA 865.

The highway veers northeastward from Bellwood to serve the borough of Tyrone, located at the junction of old US 220 and PA 453. Access to the borough is made by way of exit 48, which serves PA 453. Past Tyrone, I-99 and US 220 head through sparsely populated areas of Blair and Centre counties. For this reason, only three exits exist between Tyrone and State College: exit 52, serving PA 350 and the small community of Bald Eagle, and exits 61 and 62, which connect to US 322 and the borough of Port Matilda. Here, US 322 joins I-99 and US 220 and follows them eastward to the State College area.

At exit 68 (US 322 Bus.), I-99 merges into the Mount Nittany Expressway, an older, northerly bypass of State College. I-99, US 220, and US 322 follow the expressway to the Mount Nittany Interchange, a directional T interchange located on the northern fringe of the Pennsylvania State University campus. Beaver Stadium, the home of the Penn State Nittany Lions football team, is visible from I-99 at this point. US 322 continues east through the interchange to follow the Mount Nittany Expressway while I-99 and US 220 split from US 322 and head northeastward toward Pleasant Gap, which I-99 connects to via exit 81 and PA 26. At this point, PA 26 joins the freeway and follows it to Bellefonte, served by exit 83 and PA 550. The southern segment of I-99 ends about 1.75 miles (2.82 km) later at an intersection with Musser Lane though the divided highway continues 0.33 miles (0.53 km) northeast to an interchange with I-80, where PA 26 continues north and US 220 joins I-80 east.

The northern segment of I-99 is entirely concurrent with US 15 and starts at the junction of US 220, US 15, and I-180. I-99 crosses through mountainous terrain in Lycoming and Tioga counties, bypassing Mansfield. The route crosses the Pennsylvania–New York border north of Lawrenceville, Pennsylvania. A four-lane freeway through the Steuben County town of Lindley, I-99 crosses through a rock cut, making a large bend to the north and bypassing the hamlet of Presho. The freeway enters a partial cloverleaf interchange with County Route 5 (CR 5; Smith Road). After CR 5, I-99 turns northeast through the town of Erwin, running to the west of the Indian Hills Golf Club. Making a gradual bend further to the northeast, the freeway crosses the Canisteo River and enters the hamlet of Erwins, where it enters a diamond interchange with New York State Route 417 (NY 417; Addison Road). After NY 417, it then turns alongside Norfolk Southern Railway's Southern Tier Line (former Erie Railroad main line). Now paralleling the tracks and NY 417, I-99/US 15 crosses through Erwin, entering exit 11, which connects to NY 417 once again, next to Gang Mills Yard, the site of former Painted Post station.