It is generally accepted that high density lipoprotein cholesterol (HDL-C) is protective against cardiovascular disease, and that diabetics are at a significant excess risk of cardiovascular disease. Previous studies of HDL-C levels in noninsulin-dependent diabetics have reported divergent results, possibly due to case selection or failure to adjust for covariables known to effect HDL-C, such as obesity, cigarette smoking, alcohol intake, exercise, or exogenous estrogen use. The authors compared 97 adult noninsulin-dependent diabetics identified by history or fasting hyperglycemia from a population survey in southern California with 194 age- and sex-matched euglycemic controls from the same community. HDL-C levels were significantly lower in noninsulin-dependent diabetics of both sexes, and these differences persisted after adjustment for obesity, cigarette smoking, alcohol, exercise, and estrogen use in women. These data support the concept that reduced levels of HDL-C may be one mechanism whereby diabetics experience an excess risk of cardiovascular disease. In contrast to the published literature, HDL-C levels were not significantly different in diabetics treated with tolbutamide vs. diet therapy. This finding does not support the suggestion that the excess risk of cardiovascular disease mortality in diabetics assigned to tolbutamide reported from the University Group Diabetes Program was a consequence of tolbutamide-induced reductions in HDL-C.