Unexplained, persistent cough limits the use of angiotensin-converting enzyme (ACE) inhibitors in a significant number of patients. It has been speculated that occurrence of this adverse effect is genetically predetermined; in particular, variants of the genes encoding ACE, chymase, and B2-bradykinin receptor have been implicated. To investigate this question, we determined genotypes for common polymorphisms for these three genes in subjects with a history of ACE inhibitor-related cough. Specificity of the adverse effect was confirmed by a blinded, double-crossover design protocol in which subjects were rechallenged with either lisinopril or placebo. In 99 case subjects and 70 control subjects (who failed to develop cough on rechallenge with ACE inhibitor) thus selected, frequencies for the ACE D and I alleles were 0.56 and 0.44 (cases) and 0.56 and 0.44 (controls), respectively; frequencies for chymase A and B alleles (absence/presence of BstXI site) were 0.56 and 0.44 (cases) and 0.46 and 0.54 (controls), respectively; frequencies for B2-bradykinin receptor + and - alleles (presence/absence of a 21 to 29 nonanucleotide sequence) were 0.52 and 0.48 (cases) and 0.53 and 0.47 (controls), respectively. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for association between genotype at either gene examined and cough (adjusted for gender and age). Our data indicate that common genetic variants of ACE, chymase, and B2-bradykinin receptor do not explain the occurrence of ACE inhibitor-related cough.