Calcitonin gene-related peptide (CGRP) regulates inflammation through receptor activity-modifying protein 1 (RAMP1), a subunit of CGRP receptor complex in immune cells. In this study, we examined the role of RAMP1 in immune-mediated liver injury. RAMP1-knockout (RAMP1^-/-) mice or their wild-type counterparts (WT) were treated with Concanavalin A (Con A). Compared with WT, RAMP1^-/- mice exhibited higher levels of ALT, necrotic area, and the mRNA for pro-inflammatory cytokines including TNF and IFN. The numbers of macrophages and T cells in RAMP1^-/- mice were greater than those in WT mice. Deletion of hepatic macrophages with clodronate liposomes attenuated ALT and necrotic area in both genotypes as compared with vehicle, which was associated with reduction in TNF and IFN. By contrast, splenectomy and deletion of T cells with anti-CD4 antibody partly attenuated Con A hepatitis. Adoptive transfer of splenic T cells from RAMP1-deficient mice led to a modest increase in liver injury elicited by Con A. Co-culture of hepatic macrophages with splenic T cells led to increased cytokine expression by both cells in a RAMP1-dependent manner. Thus, immune-mediated hepatitis develops via crosstalk between immune cells. RAMP1 signaling in hepatic macrophages plays a critical role in immune-mediated hepatitis.