Patients with NPH (neutral protamine Hagedorn) insulin-dependent diabetes may have an increased risk for protamine reactions because of prior sensitization. During one year, we prospectively evaluated 50 at-risk cardiac surgery patients for clinical reactions and determined in vitro histamine release when protamine was added to a preoperative blood sample. We speculated that in vitro histamine release would predict a reaction to protamine given clinically for neutralization of heparin. Twenty-five patients randomly received prophylactic corticosteroid and/or antihistamine pretreatment for allergic reactions. The incidence of clinical reactions to protamine was 1/50 (2%) in NPH insulin-dependent diabetic patients (1/25 in pretreated patients vs 0/25 in patients not receiving pretreatment). One pretreated NPH diabetic patient released histamine in vitro but did not demonstrate clinical signs of a reaction following protamine administration. One other NPH diabetic patient pretreated with corticosteroids developed severe pulmonary hypertension despite the absence of in vitro histamine release. Therefore, in vitro histamine release does not predict protamine reactions.