Patients with type 2 diabetes (T2DM) often present a preponderance of small, dense LDL particles (small-LDL), which are associated with a high risk of myocardial infarction. Some studies suggest that PPARgamma-agonists increase LDL cholesterol but have divergent effects on various LDL subclasses in T2DM patients. We studied the effect of rosiglitazone on the LDL subclass profile in T2DM patients with verified coronary artery disease (CAD). 58 patients with T2DM (HbA1c < 8.5%) and CAD were enrolled in a 16-week, randomized, double-blind and placebo-controlled trial with rosiglitazone 8 mg/day (n = 29) or placebo (n = 29). The LDL subclass profile was measured with gel electrophoresis. Rosiglitazone improved insulin sensitivity and glycemic control. Total cholesterol did not change after rosiglitazone treatment (p = 0.062, ANCOVA adjusted for gender and baseline values), whereas LDL (including IDL) cholesterol increased from 2.33 +/- 0.48 to 2.67 +/- 0.61 mmol/l (p = 0.002 vs. baseline, p = 0.0497 vs. placebo) and large buoyant LDL (large-LDL < 250A) increased from 1.31 +/- 0.36 to 1.46 +/- 0.42 mmol/l (p = 0.010 vs. baseline, p = 0.044 vs. placebo) in the rosiglitazone group. No significant changes occurred to the concentration of small-LDL (< 250A), the average LDL particle size, or HDL or triglyceride concentrations. Whole-body insulin sensitivity was associated with the average LDL particle size after intervention in the whole population (r = 0.40, p = 0.002) and in the rosiglitazone group (r = 0.43, p = 0.020). In conclusion, in T2DM patients with CAD, rosiglitazone treatment significantly increases the concentration of large (buoyant) LDL cholesterol, but not of small dense LDL cholesterol. The long term consequences of this divergent effect of rosiglitazone on LDL subfractions require further exploration.