The requirements of complement (C) to induce systemic and cutaneous Forssman reactions were studied in inbred DHC-BA and Hartley strain guinea pigs. After intravenous injection of Forssman antibody, fatal systemic shock was associated with a marked drop in CH50, C4, and C3 and a lesser decrease in C5 hemolytic activity. Platelet counts and leukocyte counts dropped as well. With the use of the purified low molecular weight factor from cobra venom (CVF) to deplete C3, guinea pigs with less than 1% intravascular C3 were protected from lethal shock. Approximately 1% to 3% C3 activity is required for Forssman cutaneous vasculitis. These results confirm earlier studies that classical complement pathway activation occurs in Forssman shock and demonstrate the exquisite biologic efficiency of C3 in provoking the shock syndrome.