We investigated the pleiotropic effects of a calcium antagonist (amlodipine) on early atherosclerosis development in the presence and absence of an HMG-CoA-reductase inhibitor (atorvastatin) in apolipoprotein E*3-Leiden/human C-reactive protein (E3L/CRP) transgenic mice. Male E3L/CRP transgenic mice were fed a cholesterol-containing diet either with or without amlodipine and/or atorvastatin. After 31 weeks, atherosclerosis in the aortic root area was quantified. Treatment with amlodipine did not significantly lower blood pressure, but resulted in a 43% reduction (P < 0.03) of lesion area as compared with the untreated group. Treatment with atorvastatin resulted in an 80% reduction of lesion area as compared with the untreated group (P < 0.001). Combined treatment with amlodipine and atorvastatin decreased the lesion area by 93%, significantly more than either treatment alone (P < 0.008). Plasma C-reactive protein levels were mildly elevated, on average 10 ± 6 mg/L, and did not differ between groups, neither on baseline nor during treatment. Treatment with amlodipine, independently of blood pressure lowering, reduced atherosclerosis development in E3L/CRP mice. Atorvastatin had a strong anti-atherosclerotic effect, whereas co-treatment with amlodipine enhanced this effect significantly. Plasma C-reactive protein levels were not affected by any of the three treatments. Copyright © 2006 by Lippincott Williams & Wilkins.