Diabetics are at increased risk for coronary heart disease even after accounting for other risk factors, and the impact of diabetes mellitus may be particularly strong among females and at adverse levels of other risk factors. Therefore, the independent relation of diabetes to arteriographically-documented coronary artery disease (CAD) was examined in 5620 patients (18% female) referred to two Milwaukee hospitals from 1972 to 1986. As assessed by questionnaire, the prevalence of diabetes mellitus among these patients was 8% (n = 466). Diabetics had increased CAD (assessed by the number and severity of stenoses) even after accounting for levels of total and high-density lipoprotein cholesterol, triglycerides, hypertension, obesity, smoking, and alcohol consumption. In addition, regression analyses indicated that as compared with nondiabetics, female diabetics tended to have a greater increase in CAD than did male diabetics (p = 0.06 for sex x diabetes interaction). Although adverse levels of other risk factors did not increase the association between diabetes and CAD, female diabetics who were using oral hypoglycemics or insulin showed almost a two-fold increase in CAD severity (p less than 0.01). Results suggest that the higher relative risk of coronary heart disease among female (vs male) diabetics may be due to a proportionately greater increase in atherosclerosis.