The development of aortic aneurysms is a chronic process involving infiltration of inflammatory cells, degradation of the extracellular matrix and cellular transformation within the vessel wall. Calcium channel blockers exert multiple beneficial effects in the vascular system but their effect on aneurysm formation is unknown. We determine the effect of the benzothiazepine-type calcium channel blocker diltiazem in a mouse model of aneurysm formation. Aneurysm formation was induced by infusion of angiotensin II (AngII, 1.44 mg/kg/day) via osmotic minipumps for four weeks in ApoE knockout mice. Subgroups received diltiazem (100 mg/kg/day) with or without co-infusion of phenylephrine (18 mg/kg/d) to counteract the blood pressure lowering effect of the drug. Diltiazem reduced the AngII-induced hypertension and prevented aneurysm formation. Importantly, the latter effect was blood pressure independent as antagonizing the pressure effect of diltiazem with phenylephrine did not attenuate the inhibitory effect of the drug on aneurysm formation. Molecular changes in the vessel wall were examined after 6 days of AngII-treatment on equal conditions followed by real-time PCR of the aortic arch. AngII induced the expression of IL6, MCP-1, TNFa and TGFb and this effect was significantly reduced by diltiazem independent of the blood pressure. Moreover, diltiazem prevented the infiltration of inflammatory cells determined by the expression of the macrophage marker F4/80, while amounts of fibroblasts and smooth muscle cells remained unaffected at this early time point. In culture, AngII treatment of murine fibroblasts induced IL6 mRNA which could be reduced by diltiazem (10 mmol/L). Our observations indicate that diltiazem has a strong pressure-independent anti-inflammatory effect on vascular cells which prevents macrophage influx and subsequent aneurysm formation.