[Gd@C82(OH)22]n, a fullerene-based nanoparticle, exhibits potent anti-tumor effects in mouse tumor-bearing models without detectable toxicity and the pathological studies revealed a massive infiltration of leukocytes in the residual tumors of [Gd@C82(OH)22]n-treated mice. We report here that [Gd@C82(OH)22]n promotes macrophages secreting pro-inflammatory cytokines IL-6 and TNF-alpha, enhances the expression of MHC-II and costimulatory molecules such as CD40 and CD54, increases endocytosis and cell adhesion. Furthermore, [Gd@C82(OH)22]n-treated macrophages became functionally activated as illustrated by their capacity to activate allogeneic T cells. Taken together, our results indicate that [Gd@C82(OH)22]n nanoparticle is a potent activator of macrophages, which may in part account for its potent anti-tumor effect.