Effects of aromatase inhibitor (AI) therapy on the plasma lipid profile are not clear. Here the authors describe changes in fasting lipids (total cholesterol, high-density lipoprotein [HDL], low-density lipoprotein [LDL], and triglycerides) before and after 3 months of exemestane or letrozole treatment. HDL was reduced in the entire cohort (P < .001) and in the exemestane group (P < .001) but unchanged in the letrozole group (P = .169). LDL was increased in the entire cohort (P = .005) and in the letrozole group (P = .002) but unchanged in the exemestane group (P = .361). This effect was at least partially attributable to washout of tamoxifen as only patients with prior use of tamoxifen experienced a significant increase in LDL. Baseline HDL was an independent predictor of the change in HDL (r2 = −0.128, P < .001), and prior tamoxifen use was associated with greater increases in LDL (r2 = 0.057, P < .001). Use of lipid-altering medications did not protect against the exemestane-induced drop in HDL or the increase in LDL observed in women with prior use of tamoxifen taking letrozole. In conclusion, AI treatment and/or washout of tamoxifen induced detrimental changes in the lipid profile of postmenopausal women with breast cancer.