Aims Inflammation plays an important role in the neointima formation of grafted veins. However, the initiation of inflammation in grafted veins is still unclear. Here, we investigated the role and underlying mechanism of an innate immunity signalling protein, caspase-associated recruitment domain 9 (CARD9) in vein grafts in mice. Methods and results In early murine vein grafts, we observed robust death of smooth muscle cells (SMCs), which was accompanied by infiltration of macrophages and expression of pro-inflammatory cytokines. Meanwhile, SMC necrosis was associated with the expression of pro-inflammatory cytokines in macrophages in vitro. To explore the mediators of necrotic SMC-induced inflammation in grafted veins from mice, we examined the expression of CARD family proteins and found CARD9 highly expressed in infiltrated macrophages of grafted veins. CARD9-knockout (KO) inhibited necrotic SMC-induced pro-inflammatory cytokine expression and NF-kappa B activation. Furthermore, CARD9-KO suppressed necrotic SMC-induced expression of VEGF in macrophages. Finally, CARD9-KO decreased neointima formation of grafted veins in mice. Conclusion The innate immune protein CARD9 in macrophages may mediate necrotic SMC-induced inflammation by activating NF-kappa B and contributed to neointima formation in the vein grafts.