OBJECTIVE: This study was undertaken to assess the effect of pioglitazone hydrochloride and rosiglitazone maleate on blood lipid levels and glycemic control when these drugs are used as adjunctive therapy in type 2 diabetes. RESEARCH DESIGN AND METHODS: Patients with type 2 diabetes receiving metformin and/or sulfonylurea (n = 829) were evaluated in this national, multicenter, retrospective study. Medical records from 318 endocrinology practices in the USA were randomly selected and screened for study inclusion. Data related to patient demographics and laboratory data were extracted from medical records and analyzed for primary and secondary outcomes. MAIN OUTCOME MEASURES: The primary study outcome was the mean change in plasma rosiglitazone was associated with no significant triglyceride (TG) levels. Secondary outcome measures included mean changes in total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) concentrations and hemoglobin A1C levels. RESULTS: With pioglitazone, TG levels declined by a mean of 51.5 mg/dl (P < 0.001), HDL-C levels rose by 3.3mg/dl (P < 0.001), and no change was seen in LDL-C or TChol. Treatment with change in TG levels and a 1.5mg/dl mean increase in HDL-C (P < 0.001). Furthermore, rosiglitazone therapy was associated with an 8 mg/dl mean increase in TChol (P < 0.001), and a 5.8 mg/dl mean increase in LDL-C (P < 0.001). Hemoglobin A1C levels were significantly reduced by approximately 1% within thiazolidinedione (TZD) cohorts (P < 0.001), but were not significantly different between study groups (P = 0.257). CONCLUSIONS: Results from this study suggest that pioglitazone has a more favorable effect on lipid profiles of patients with type 2 diabetes compared with rosiglitazone. In particular, differences were observed in TG and LDL-C levels. Both TZDs were equivalent at reducing hemoglobin A1C levels. These differences in lipid effects may have an impact on cardiovascular outcomes. The full clinical importance of these lipid alterations must be further assessed in prospective trials.