Serum sickness is a type III hypersensitivity reaction that results from the injection of heterologous or foreign protein or serum. Reactions secondary to the administration of nonprotein drugs are clinically similar to serum sickness reactions.

Historically, the term serum sickness connotes a self-limited immune complex disease caused by exposure to foreign proteins or haptens. Immune complex formation is a common event and does not typically cause symptoms. However, an immune reaction can occur, as in the case of serum sickness

Von Pirquet and Shick first described the syndrome in 1905, describing fever, skin eruptions (mainly consisting of urticaria), joint pain, and lymphadenopathy in regions draining the site of injection after patients were given antitoxin in the form of horse serum. Later, physicians reported a similar clinical picture after the injection of other equine-based antitoxins and antivenins.[2] Certain medications (eg, penicillin, nonsteroidal anti-inflammatory drugs [NSAIDs]) have also been associated with serum sickness–like disease.

Identifying serum sickness was a landmark observation in understanding immune complex diseases.