Non-insulin-dependent diabetes mellitus (NIDDM) confers myocardial infarction (MI) risk unexplained by known factors. In 356 NIDDM patients and 1,087 people with normal glucose tolerance, we investigated the association between MI risk and polymorphism at codon 360 in the apolipoprotein A-IV (apoA-IV) gene. During 1984-1992, MI was diagnosed in 84 diabetic and in 106 nondiabetic people. The risk of MI did not differ by apoA-IV phenotype in nondiabetic people; however, in NIDDM patients, those with the apoA-IV 1-2 phenotype had 2.8 (95% confidence interval: 1.4-5.6) higher MI risk than those with the 1-1 phenotype, adjusting for age, gender, ethnicity, hypertension, smoking, body mass index, fat centrality, and low-density lipoprotein and high-density lipoprotein cholesterol. The risk of MI was particularly high in obese NIDDM patients with the apoA-IV 1-2 phenotype: 5.1 (2.4-11.2) times that in obese apoA-IV 1-1 NIDDM patients and 7.7 (3.6-16.7) times that in lean nondiabetic people. The effect of apoA-IV 1-2 did not appear to be a part of the insulin-resistance syndrome nor was it dependent on diabetes duration or control. One half of the excess MI risk in the diabetic population studied was explained by the apoA-IV 1-2 phenotype. These results indicate that approximately 17% of NIDDM patients have a high MI risk apoA-IV phenotype that is particularly deleterious in obese patients.