Chromosome 17q21-23 harbors genes for platelet glycoprotein IIIa and angiotensin-converting enzyme (ACE), which are polymorphic for alleles Pl(A2) and ACE "D." These alleles have been independently and often associated with ischemic coronary artery disease (CAD). We sought to determine if the Pl(A2) and ACE D polymorphisms were risk factors for recurrent coronary events. In the Cholesterol And Recurrent Events (CARE) trial, 4,159 men and women with documented myocardial infarction (MI) were randomized to receive either placebo or pravastatin, and were followed prospectively for 5 years. Pl(A) and ACE genotypes were determined in 767 patients: 385 cases who had experienced a recurrent primary event (death due to coronary disease or nonfatal MI), and 382 age- and gender-matched controls. In patients receiving placebo, the Pl(A1,A2) genotype conferred a relative risk (RR) of 1.38 (confidence intervals [CI] 1.04 to 1.83; p = 0.028; adjusted RR = 1.32, CI = 0.99 to 1.76; p = 0.058]) for the primary end point. Compared with the placebo group, pravastatin reduced the excess RR of coronary disease death and recurrent MI in the Pl(A1,A2) patient population by 31% (p = 0.06). The ACE D allele appeared to have modestly additive effects on the Pl(A1,A2) risk. Among the Pl(A1,A2) patients, pravastatin had little effect on the risk of recurrent events with the ACE II genotype, but reduced the adjusted RR from 1.42 (placebo) to 0.58 for ACE ID patients, and from 1.56 (placebo) to 0.83 for ACE DD. The Pl(A1,A2) genotype was associated with an excess of recurrent coronary events in patients after MI who did not receive pravastatin, and the ACE D allele added to this risk. These data suggest that it would be important to perform a larger study to address the potential role of these genotypes in therapeutic decision making.