We examined the relationship of maturity-onset clinical diabetes mellitus with the subsequent incidence of coronary heart disease, stroke, total cardiovascular mortality, and all-cause mortality in a cohort of 116,177 US women who were 30 to 55 years of age and free of known coronary heart disease, stroke, and cancer in 1976. During 8 years of follow-up (889 255 person-years), we identified 338 nonfatal myocardial infarctions, 111 coronary deaths, 259 strokes, 238 cardiovascular deaths, and 1349 deaths from all causes. Diabetes was associated with a markedly increased risk of nonfatal myocardial infarction and fatal coronary heart disease (age-adjusted relative risk [RR] = 6.7; 95% confidence interval [CI], 5.3 to 8.4), ischemic stroke (RR = 5.4; 95% CI, 3.3 to 9.0), total cardiovascular mortality (RR = 6.3; 95% CI, 4.6 to 8.6), and all-cause mortality (RR = 3.0; 95% CI, 2.5 to 3.7). A major independent effect of diabetes persisted in multivariate analyses after simultaneous control for other known coronary risk factors (for these end points, RR [95% CI] = 3.1 [2.3 to 4.2], 3.0 [1.6 to 5.7], 3.0 [1.9 to 4.8], and 1.9 [1.4 to 2.4], respectively). The absolute excess coronary risk due to diabetes was greater in the presence of other risk factors, including cigarette smoking, hypertension, and obesity. These prospective data indicate that maturity-onset clinical diabetes is a strong determinant of coronary heart disease, ischemic stroke, and cardiovascular mortality among middle-aged women. The adverse effect of diabetes is amplified in the presence of other cardiovascular risk factors, many of which are modifiable.