Erythema multiforme (EM) is an immune-mediated inflammatory skin condition associated with several viral infections, that appears with red patches evolving into target lesions, typically on both hands. It is typically associated with infection by either herpes simplex virus or Mycoplasma pneumoniae.

It is a type IV hypersensitivity reaction in which T-lymphocytes target skin keratinocytes due to the presence of specific proteins that resemble antigens of HSV, Mycoplasma, or other pathogens and foreign substances. It is an uncommon disorder, with peak incidence in the second and third decades of life. The disorder has various forms or presentations, which its name reflects (multiforme, "multiform", from multi- + formis). Target lesions are a typical manifestation. Two standard types, one mild to moderate and one severe, are recognized (erythema multiforme minor and erythema multiforme major), as well as several rare and atypical types.

The condition varies from a mild, self-limited rash (E. multiforme minor) to a severe, life-threatening form known as erythema multiforme major (or erythema multiforme majus) that also involves mucous membranes. Consensus classification:

The mild form usually presents with mildly itchy (but itching can be very severe), pink-red blotches, symmetrically arranged and starting on the extremities. It often takes on the classical "target lesion" appearance, with a pink-red ring around a pale center. Resolution within 7–10 days is the norm.

Individuals with persistent (chronic) erythema multiforme will often have a lesion form at an injury site, e.g. a minor scratch or abrasion, within a week. Irritation or even pressure from clothing will cause the erythema sore to continue to expand along its margins for weeks or months, long after the original sore at the center heals.^{[citation needed]}

Erythema multiforme typically arises as a type IV hypersensitivity reaction to certain infections or, rarely, certain medications. The most common trigger is an infection with any type of the herpes simplex virus. The second most common trigger, and the most common in children, is infection with Mycoplasma pneumoniae, most commonly as an atypical pneumonia. When the body encounters these triggers, the immune system responds by activating various cells to fight off what it perceives as harmful invaders. Certain medications and other infections are also sometimes identified as causes of erythema multiforme, and while some experts doubt any true association with EM, others disagree, citing the lack of any HSV DNA found in cases of drug-associated EM.

The pathogenic immune response in EM involves both CD4+ helper T cells and CD8+ cytotoxic T cells, which orchestrate a type IV hypersensitivity reaction. Upon activation, these T cells release proinflammatory cytokines such as IFN-γ and TNF-α. Despite the known association with IFN-γ, erythema multiforme is not considered a humorally-mediated autoimmune reaction.

Rarely, some patients may suffer from a persistent and treatment-resistant form of erythema multiforme caused by the Epstein-Barr virus. This pathology is distinct from the recurrent cases that sometimes arise from HSV-associated EM.