Cerebral aneurysm (CA) has a high prevalence and causes a fatal subarachnoid hemorrhage. Although CA is a socially important disease, there are currently no medical treatments for CA, except for surgical procedures, because the detailed mechanisms of CA formation remain unclear. From recent studies, we propose that CA is a chronic inflammatory disease of the arterial walls and various inflammation-related factors participate in its pathogenesis. Mast cells are well recognized as major inflammatory cells related to allergic inflammation. Mast cells have numerous cytoplasmic granules that contain various cytokines. Recent studies have revealed that mast cells contribute to various vascular diseases through degranulation and release of cytokines. In the present study, we examined the role of mast cells in the pathogenesis of CA using an experimental rat model. The number of mast cells was significantly increased in CA walls during CA formation. Inhibitors of mast cell degranulation effectively inhibited the size and medial thinning of induced CA through the inhibition of chronic inflammation, as evaluated by nuclear factor-kappa B activation, macrophage infiltration, and the expression of monocyte chemoattractant protein-1, matrix metalloproteinases (MMPs), and interleukin-1β. Furthermore, an in vitro study revealed that the degranulation of mast cells induced the expression and activation of MMP-2, -9, and inducible nitric oxide synthase in primary cultured smooth muscle cells from rat intracranial arteries. These results suggest that mast cells contribute to the pathogenesis of CA through the induction of inflammation and that inhibitors of mast cell degranulation can be therapeutic drugs for CA.