Macrophages are considered promoters of fibroblast proliferation; however, suppression by activated macrophages may outweigh this effect. Activated murine peritoneal macrophages obtained by in vivo exposure to C. parvum or by in vitro LPS-activation of thioglycollate-induced macrophages, were tested for their effect on normal syngeneic dermal fibroblasts. C. parvum-activated macrophages, but not resident peritoneal macrophages suppressed fibroblast proliferation. Similarly, macrophages activated in vitro by LPS, but not those unexposed to LPS, suppressed fibroblast proliferation. Catalase partially protected fibroblasts from suppression by either activated macrophage population, suggesting involvement of H2O2 in the suppression. The effect of cyclooxygenase inhibitors on the suppression was also tested. Indomethacin, acetylsalicylic acid, or eicosatetraynoic acid, all partially protected the fibroblasts from macrophage-mediated suppression. Prostaglandins E2, E1, and F2α, added exogenously at concentrations as high as 10-6M, failed to suppress the proliferation of the fibroblasts. These findings suggest that a nonprostaglandin product of the cyclooxygenase pathway is involved in macrophage-mediated suppression of fibroblast proliferation.