Background: Metformin and rosiglitazone both improve glycemic control in type 2 diabetes mellitus, however may possess different anti-inflammatory and anti-atherosclerotic properties. We investigated the effects of these medications on high-sensitivity C-reactive protein (hsCRP) and carotid artery intima-media thickness (CIMT) to determine their relative potential to reduce cardiovascular risk independent of their antihyperglycemic actions. Methods: Ninety-two subjects with suboptimally controlled diabetes mellitus (hemoglobin A1c [HbA1c] >7.0%) were assigned to therapy with either rosiglitazone 4 mg once daily or metformin 850 mg twice daily for 24 weeks. The primary end point was the change in hsCRP after 24 weeks. The change in CIMT was prespecified as a secondary end point. Results: Metformin and rosiglitazone treatment led to similar significant improvements in glycemic control (HbA1c -1.08% in the rosiglitazone group and -1.18% in the metformin group, P = nonsignificant). High-sensitivity C-reactive protein levels decreased by an average of 68% in the rosiglitazone group (5.99 ± 0.88 to 1.91 ± 0.28 mg/L, P < .001), compared with a nonsignificant 4% reduction in hsCRP with metformin (5.69 ± 0.83 to 5.46 ± 0.92 mg/L; P = nonsignificant). Maximal CIMT progressed in the metformin group (+0.084 ± 0.038 mm), whereas regression of maximal CIMT was observed in the rosiglitazone group (-0.037 ± 0.031 mm; P = .02 for the between group comparison). Similar changes were observed for mean CIMT. The change in hsCRP and maximal CIMT were related in a multivariable model controlling for changes in HbA1c and lipid parameters (r = .31; P = .01). Conclusions: Rosiglitazone, compared to metformin, induced a prompt and profound reduction in hsCRP levels independent of its effect on glycemia. This change was associated with regression of CIMT after 24 weeks.