OBJECTIVE - To evaluate the association of postmenopausal hormone replacement with plasma lipids in diabetic women. RESEARCH DESIGN AND METHODS - Cross- sectional data from a multiracial population study were used to evaluate the relationship of hormone replacement status with plasma lipids in diabetic (n = 694) versus nondiabetic (n = 5,321) postmenopausal women. RESULTS - Although diabetic women who currently used hormone replacement had higher adjusted mean HDL cholesterol levels than those who did not (56.9 vs. 53.6 mg/dl), they had proportionately lower hormone-related increases in HDL, HDL, and HDL, cholesterol than did nondiabetic women (HDL cholesterol 64.9 [current users] vs. 55.7 mg/dl [those who never used hormones]). There was a trend toward greater triglyceride values with hormones replacement in diabetic women (156.6 [current users] vs. 125.4 mg/dl [those who never used hormones]) than in nondiabetic women (143.3 [current users] vs. 123.7 mg/dl [those who never used hormones]), LDL cholesterol and apolipoprotein B levels were lower and apolipoprotein A-1 levels were higher with hormone replacement to a similar degree in diabetic and nondiabetic women. CONCLUSIONS - Diabetic women appear to have a blunted response to the HDL-raising effects of estrogen and an exaggerated hypertriglyceridemic response. This may results in attenuated cardioprotection from postmenopausal hormone replacement therapy and potentially an increased risk of acute pancreatitis from hypertriglyceridemia. The risks and benefits of postmenopausal hormone replacement need to be carefully weighed in diabetic women.