Background: Mechanisms underlying biological effects of statin and angiotensin converting enzyme inhibitor therapies differ. Therefore, we compared vascular and metabolic responses to these therapies either alone or in combination in type II diabetic patients. Methods: This was a randomized, double-blind, placebo-controlled cross-over trial with three treatment arms and three washout periods. 50 type II diabetic patients were given simvastatin 20 mg and placebo, simvastatin 20 mg and ramipril 10 mg, or ramipril 10 mg and placebo daily during each 2 month treatment period. Results: All three treatment arms significantly improved flow-mediated dilator response to hyperemia relative to baseline measurements. However, these parameters were changed to a greater extent with combined therapy when compared with simvastatin or ramipril alone (P<0.001 by ANOVA). When compared with simvastatin or ramipril alone, combined therapy significantly reduced high sensitivity C-reactive protein levels (P=0.004 by ANOVA). The three therapies did not significantly change insulin and glucose levels relative to baseline measurements. Interestingly, combined therapy or ramipril alone significantly increased plasma adiponectin levels and insulin sensitivity (QUICKI).These changes were significantly greater than in the group treated with simvastatin alone (P=0.013 for adiponectin and P=0.015 for QUICKI by ANOVA). Following combined therapy, there were significant correlations between the percent changes in adiponectin and insulin levels (r=-0.402 and p=0.004) or QUICKI (r=0.374 and p=0.008) and following ramipril alone therapy, there were significant correlations between the percent changes in adiponectin and insulin levels (r=-0.510 and p<0.001) or QUICKI (r=0.407 and p=0.003). There were no significant correlations between these changes and reduction of systolic and diastolic blood pressure (-0.201���r���0.266) following combined or ramipril alone therapy. Conclusions: Ramipril combined with simvastatin improves endothelial function and reduces inflammatory marker to a greater extent than monotherapy with either drug in type II diabetic patients.