T cell Ig and mucin domain (TIM)-4 is involved in immune regulation. However, the pathological function of TIM-4 has not been understood and remains to be clarified in various disease models. In this study, DBA/1 mice were treated with anti-TIM-4 mAb during the induction or effector phase of collagen-induced arthritis (CIA). Anti-TIM-4 treatment in the induction phase exacerbated the development of CIA. In vitro experiments suggest that CD4 T cells bind to TIM-4 on APCs, which induces inhibitory effect to CD4 T cells. In contrast, therapeutic treatment with anti-TIM-4 mAb just before or after the onset or even at later stage of CIA significantly suppressed the development and progression by reducing proinflammatory cytokines in the ankle joints without affecting T or B cell responses. Consistently, clinical arthritis scores of collagen Ab-induced arthritis, which is not mediated by T or B cells, were significantly reduced in anti-TIM-4-treated mice with a concomitant decrease of proinflammatory cytokines in the joints. In vitro, macrophages secreted proinflammatory cytokines in response to TIM-4-Ig protein and LPS, which were reduced by the anti-TIM-4 mAb. The anti-TIM-4 mAb also inhibited the differentiation and bone-resorbing activity of osteoclasts. These results indicate that TIM-4 has two distinct functions depending on the stage of arthritis. The therapeutic effect of anti-TIM-4 mAb on arthritis is mediated by the inhibition of proinflammatory cytokine production by inflammatory cells, osteoclast differentiation, and bone resorption, suggesting that TIM-4 might be an appropriate target for the therapeutic treatment of arthritis.