Patients with neutral protamine Hagedorn and protamine-zinc insulin-dependent diabetes, a history of fish allergy, or prior vasectomy have been reported to be at an increased risk for protamine reactions after cardiopulmonary bypass because of prior sensitization. We prospectively evaluated cardiac surgical patients with prior vasectomies and fish allergies and retrospectively evaluated a cohort of 3245 consecutive cardiac surgical patients requiring cardiopulmonary bypass over a 2-year period for protamine-containing insulin use and clinical evidence of adverse reactions after protamine administration for heparin reversal after cardiopulmonary bypass. Clinical reactions to protamine did not occur in six patients with fish allergies or 16 patients with prior vasectomies. There was one reaction (0.6%) in 160 patients with neutral protamine Hagedorn insulin-dependent diabetes. The incidence of clinical reactions in the other patients was 2/3085 (0.06%). The incidence of clinical reactions in the patients with neutral protamine Hagedorn insulin-dependent diabetes is not significantly different from that in other patients. We conclude that prior neutral protamine Hagedorn insulin use, a history of fish allergy, or prior vasectomy does not represent a contraindication to protamine administration after cardiopulmonary bypass.