In 27 patients with non-insulin-dependent diabetes mellitus, we determined fasting serum glucose, hemoglobin A1, body weight, serum triglycerides, cholesterol, low-density lipoprotein cholesterol (LDL-chol), high-density lipoprotein cholesterol (HDL-chol), and very-low-density lipoprotein cholesterol during treatment with insulin and several months after changing treatment to chlorpropamide. In five patients, diabetic control deteriorated to the point where insulin was reinitiated. In the remaining 22 patients, despite a significant decrease in weight (122 +/- 5 vs. 114 +/- 5% ideal body wt; P less than .025) on chlorpropamide, HDL-chol fell from 49 +/- 4 to 40 +/- 4 mg/dl (P less than .01) when therapy was modified from insulin to the sulfonylurea. There was a concomitant increase in LDL-chol:HDL-chol from 3.6 +/- 0.3 to 4.4 +/- 0.5 (P less than .05). In the 5 patients in whom insulin was reinstituted, HDL-chol increased to its previous level on insulin (P less than .05). Changing antidiabetic medication from insulin to sulfonylureas may alter the lipoproteins in a manner that increases cardiovascular risk.