Protamine insulin use may immunologically sensitize patients to protamine, leading to anaphylactoid reactions upon subsequent exposure to protamine sulfate during cardiac catheterization or cardiovascular surgery. The risk of such reactions in protamine insulin-dependent patients is uncertain. One catheterization study reported a 50-fold greater risk while a second showed no increased risk! To clarify the risk, the records of 7,750 cardiac catheterization procedures between 1984 and 1987 were analyzed for presence of NPH or PZI insulin use, protamine administration, and any complications or adverse reactions. Protamine was administered in 3,341/7,750 procedures (43%), including 171 in diabetics receiving NPH insulin. Adverse reactions to protamine occurred in 2/3,170 noninsulin patients, 0.06%, and adverse reactions due to probable NPH insulin sensitization occurred in 1/171,0.6%, of NPH diabetics, p =.034. Meta-analysis of risk showed an odds ratio of 7.96 for the NPH diabetic patients, and combining these results with the other large series in the literature (269 NPH diabetics total) showed an odds ratio of 4.19 compared to a non-NPH insulin group. Meta-analysis of the surgical literature showed the risk in surgical patients to be 2.1% in NPH patients versus 0.12% with no NPH, with an odds ratio of 15.52. The greater incidence in surgical patients may be due to protamine sensitization at prior catheterization and to the larger dose of protamine administered to surgical patients.