Serum sickness is a Type III hypersensitivity reaction caused by the formation and deposition of antigen-antibody immune complexes in tissues. It classically occurred after administration of heterologous (animal-derived) serum proteins (e.g., horse anti-thymocyte globulin, antivenom, anti-diphtheria serum) but now more commonly presents as serum sickness-like reaction (SSLR) triggered by medications (cefaclor, TMP-SMX, penicillin, amoxicillin), monoclonal antibodies (rituximab, infliximab), or blood products. The pathophysiology follows: foreign protein acts as antigen → IgG/IgM antibody formation (7-14 days for primary exposure, 1-3 days for re-exposure) → circulating immune complexes form → complexes deposit in vessel walls, glomeruli, joints, and skin → complement activation (C3a, C5a) and Fc-receptor engagement recruit neutrophils and macrophages → inflammatory tissue damage. The classic triad is fever, urticarial rash (often with serpiginous borders), and polyarthralgia/polyarthritis appearing 7-14 days after first exposure. Complement levels (C3, C4) are consumed and decreased. Unlike anaphylaxis (Type I, IgE-mediated, minutes), serum sickness is delayed (days to weeks) and immune complex-mediated.