Trimethoprim/sulfamethoxazole, sold under the trade names Bactrim, Cotrim (a short form of the British Approved Name, Co-trimoxazole) and Septra, among others, is a fixed-dose combination antibiotic medication used to treat a variety of bacterial infections. It consists of one part trimethoprim to five parts sulfamethoxazole. It is used to treat urinary tract infections, methicillin-resistant Staphylococcus aureus (MRSA) skin infections, travelers' diarrhea, respiratory tract infections, and cholera, among others. It is used both to treat and prevent pneumocystis pneumonia and toxoplasmosis in people with HIV/AIDS and other causes of immunosuppression. It can be given orally (swallowed by mouth) or intravenous infusion (slowly injected into a vein with an IV).

Trimethoprim/sulfamethoxazole is on the World Health Organization's List of Essential Medicines. It is available as a generic medication. In 2023, it was the 128th most commonly prescribed medication in the United States, with more than 4 million prescriptions.

Trimethoprim/sulfamethoxazole generally kills bacteria, by blocking the microorganisms' ability to make and to use folate.

Trimethoprim/sulfamethoxazole (TMP/SMX) is the medicine most commonly used to prevent Pneumocystis jirovecii pneumonia (PCP) People who get Pneumocystis pneumonia have a medical condition that weakens their immune system, like HIV/AIDS, or take medicines (such as corticosteroid, monoclonal antibody and immunosuppressants) that reduce the body's ability to fight bacterial and viral infections. People with HIV/AIDS are less likely to get Pneumocystis pneumonia as a result of antiretroviral therapy (ART). However, Pneumocystis pneumonia is still a substantial public health problem. Most of what is scientifically known about Pneumocystis pneumonia and its treatment comes from studying people with HIV/AIDS.

Organisms against which trimethoprim/sulfamethoxazole can be effective include:

The only notable nonsusceptible organisms are Pseudomonas aeruginosa, the mycoplasmae and Francisella tularensis (the causative organism of tularaemia).

Its use during pregnancy is contraindicated, although it has been placed in Australian pregnancy category C. Its use during the first trimester (during organogenesis) and 12 weeks prior to pregnancy has been associated with an increased risk of congenital malformations, especially malformations associated with maternal folic acid deficiency (which is most likely related to the mechanism of action of co-trimoxazole) such as neural tube defects such as spina bifida, cardiovascular malformations (e.g. Ebstein's anomaly), urinary tract defects, oral clefts, and club foot in epidemiological studies. Its use later on during pregnancy also increases the risk of preterm labour (odds ratio: 1.51) and low birth weight (odds ratio: 1.67). Animal studies have yielded similarly discouraging results.

It appears to be safe for use during breastfeeding as long as the baby is healthy.