Rosiglitazone may increase cardiovascular risk in patients with type 2 diabetes. Yet, its effects on atherogenic dyslipidemia are still not fully elucidated. In a prospective open-label study rosiglitazone (4 mg/day for 12 weeks) was added to a maximum of 2 oral antidiabetic drugs in 18 diabetic patients. We evaluated the effects on plasma lipids before and after an oral fat load. The size and subclasses of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) were also determined (by gradient gel electrophoresis). Rosiglitazone improved glycosylated hemoglobin ([HbA1c] P = .0023), without significant effects on fasting and postprandial plasma lipids. Fasting LDL size increased (+1.4%, P = .034), with less small, dense LDL-IIIA (-25.1%, P = .018). Postprandially, larger HDL-2b reduced (-8.7%, P = .006) and smaller HDL-3b increased (+12.2%, P = .05), without any effects on HDL size. Rosiglitazone led to antiatherogenic changes in LDL size and subclasses, with proatherogenic changes in HDL subclasses, despite no effects on plasma lipids. Their clinical relevance remains to be established.