Systemic toxic were encountered in eight of 10,469 patients during or immediately following the intramuscular injection of 4,800,000 units of procaine penicillin G for the treatment of gonorrhea. Fear of imminent death, visual and auditory disturbances, violent combativeness, confusion, disorientation, and restlessness, disturbance in taste, cardiovascular changes, and grand mal seizures are the principal manifestations; these usually subside in two to 10 minutes spontaneously or after treatment. Symptoms and signs closely parallel systemic toxic reactions to local anesthetics. Pharmacokinetic analysis in dogs using 14C-procaine and 14C-procaine penicillin G showed rapid distribution of labeled drugs from plasma to cerebrospinal fluid for the intravenous as compared to the intramuscular route of administration. The animal studies were consistent with the hypothesis that the inadvertent intravenous administration of procaine penicillin G is responsible for the systemic toxic reactions. Plasma procainesterase (pseudocholinesterase) activity was assayed with an ultraviolet spectroscopic method. Substrates were procaine and procaine penicillin G. The plasma procainesterase activity of patients who had experienced systemic toxic reactions was significantly decreased as compared to that of controls, an observation not previously reported.