Objective: Lowering LDL-cholesterol by statins has been proven to be associated with reduction of proinflammatory regulators e.g. activation of the transcription factor NF-κB. To our knowledge, anti-inflammatory potential of newer cholesterol lowering agents such as ezetimibe is less intensively studied. Therefore we analyzed the effects of equipotent LDL-lowering therapy with simvastatin alone compared to a combination with ezetimibe on NF-κB activation in peripheral blood mononuclear cells (PBMCs) of patients with type 2 diabetes. Methods: Thirty-one patients with type 2 diabetes were included in a double-blind, randomized trial receiving either 80 mg simvastatin (sim80; n = 10) or a combination of 10 mg simvastatin and 10 mg ezetimibe (sim10eze10; n = 11) or placebo (n = 9) for eight weeks. NF-κB binding activity and inflammatory markers (IL-6, hsCRP) were analyzed at baseline and after eight weeks of treatment. NF-κB binding activity was analyzed by electrophoretic mobility shift assay. IL-6 and hsCRP were measured by ELISA. Results: After eight weeks of treatment LDL-cholesterol was lowered to the same extent in both treatment groups (p = 0.40) but not in placebo. However, patients taking sim80 showed a significant reduction of mononuclear NF-κB binding activity compared to baseline (p = 0.009) while no effect was observed in the sim10eze10 group (p = 0.79). Similar differences in anti-inflammatory effects were also observed when analyzing hsCRP (sim80: p = 0.03; sim10eze10: p = 0.40) and IL-6 levels (sim80: p = 0.15; sim10eze10: p = 0.95). Conclusion: High dose simvastatin therapy reduces proinflammatory transcription factor NF-κB binding activity and hsCRP levels, while combination of low dose simvastatin with ezetimibe resulting in a similar LDL-reduction does not affect these inflammatory markers.