CD4 + autoreactive T cells are a major cell population in regulating immune responses to altered autologous neoplastic cells. Normal autoreactive T cells recognize major histocompatibility complex (MHC) class II molecules in association with self-peptides on antigen-presenting cells, such as macrophages (MΦ). Tumor-bearing hosts (TBH) have decreased autoreactivity partly because tumors increase MΦ secretion of suppressor molecules like prostaglandin E 2 (PGE 2 ) and decrease MΦ MHC class II expression. Because interleukin (IL)-10, a cytokine produced by T cells, MΦ, and tumor cells, inhibits production of most MΦ suppressor molecules, we determined if IL-10 could reverse tumor-induced murine splenic MΦ-mediated suppression of autoreactive T cell proliferation. Tumor growth enhanced activated MΦ production of PGE 2 , nitric oxide, and tumor necrosis factor-α (TNF-α). IL-10 strongly reduced or inhibited MΦ production of these molecules. When added to pure normal host (NH) CD4 + T cells, NH syngeneic splenic MΦ stimulated autoreactive T cell proliferation more than did TBH splenic MΦ. Exogenous IL-10 or MΦ preincubation with IL-10 restored TBH MΦ-stimulated autoreactivity to normal levels. IL-10 treatment had little or no effect on NH MΦ-stimulated autoreactivity. IL-10 inhibited TBH MΦ secretion of suppressor molecules in T cell proliferation assays because supernatants from IL-10-pretreated TBH MΦ-syngeneic NH T cell cultures had decreased levels of suppressor molecules. When endogenous IL-10 activity was neutralized with anti-IL-10 monoclonal antibody, autoreactive T cell proliferation stimulated by NH or TBH MΦ was slightly, but significantly decreased. Although IL-10 is known to inhibit MΦ foreign antigen-presenting cell-dependent T cell proliferation, this study shows that IL-10 restores autoreactive T cell functions during tumor growth by counteracting MΦ production of inhibitory molecules. These data suggest that IL-10 up-regulates anti-cancer autoreactive T cell responses by down-regulating suppressor MΦ activity.