Abdominal aortic aneurysm is an important manifestation of arteriosclerosis with increasing incidence in the western world. Progressive inflammatory processes involving infiltration and differentiation of monocytes into the vessel wall, proliferation and migration of smooth muscle cells and eventually the degradation of the internal elastic lamina are causal for aneurysm formation. Since calcium channel blockers exert multiple beneficial effects in the vascular system we investigated the effect of the benzothiazepine-type calcium channel blocker diltiazem (DIL) on aneurysm formation. Angiotensin II infusion (ATII, 4 weeks, 1.44 mg/kg bw/d) induced massive aneurysm formation in ApoE-deficient mice that was blocked by co-treatment with DIL (100 mg/kg bw/day). Additional treatment with phenylephrine (PHE, 18 mg/kg bw/d) to counteract the blood pressure-lowering effect of DIL had no influence on its beneficial effect. Moreover DIL prevented the ATII-induced mRNA expression of pro-inflammatory cytokines in the aortic arch after 6 days of ATII treatment due to a reduction in the amount of locally infiltrating macrophages which was accompanied by attenuated systemic CCL12 serum level. Ex vivo, DIL (10 µM) did not reduce the ATII-induced (100 nM) expression of promigratory chemokine CCL2 and proinflammatory cytokine IL-6 of vascular segments in organ culture or vascular smooth muscle cells. Moreover, DIL (30 µM) did not affect the recruitement of Ly6C+-monocyte into subcutaneously implanted matrigel plugs filled with CCL2 (600 ng/ml) in ApoE-deficient mice. In contrast, in peritoneal macrophages and RAW264.7 cells, DIL prevented the IL-6-induced (10 ng/ml) mRNA expression of IL-1β and CCL12. As underlying mechanism, DIL abrogated the IL-6 induced activation of AP-1 promoter without affecting NF-kB activity as well as phosphorylation and nuclear translocation of MAPK1 and Stat3 or intracellular calcium. These observations indicate that DIL prevents aneurysm formation by a mechanism independent of its blood pressure and intracellular calcium lowering effects.