Patients with nephrotic syndrome (NS) are believed to be at increased risk of atherosclerosis and coronary heart disease (CHD), although existing evidence for this association has not been persuasive. The risk of CHD among 142 persons with NS documented by protein-uria > or = 3.5 g daily was compared with that among 142 matched controls randomly selected from the membership of a large Northern California health plan. Controls were matched for sex, year of birth, and presence in the health plan when the referent case was diagnosed. No diabetics were included in this study. Mean follow-up for nonfatal CHD events was 5.6 years for NS subjects and 11.2 years for controls. Among the NS subjects myocardial infarction (MI) developed in 11, and there were 58 deaths, seven because of CHD. Among the controls, there were four MIs and 10 deaths, three because of CHD. In matched-pair analysis, there were 11 MIs among NS subjects and none among controls [P = 0.001, lower bound of 95% confidence interval for relative risk (CI), 2.8]. In an unmatched analysis adjusted for hypertension and smoking at diagnosis of NS, the relative risk of MI was 5.5 (95% CI 1.6 to 18.3) and the relative risk of coronary death was 2.8 (95% CI 0.7 to 11.3). Omitting data of NS subjects with minimal change disease and systemic lupus erythematosus yielded similar results. These data suggest that persons with NS are at increased risk of CHD.