Increased collagen deposition is a common feature of granulomatous and nongranulomatous inflammation associated with certain types of cell-mediated immune reactions in vivo. In the present study, we found that normal human peripheral blood mononuclear leukocytes cultured in vitro and stimulated by antigens or T cell mitogens release a 100 to 170 K m.w., heat-labile, trypsin-sensitive protein that stimulates dermal fibroblasts to produce increased quantities of type I and III collagens. Our data suggest that this collagen production protein is of T lymphocyte origin and that it preferentially stimulates production of collagen. We also observed that human mononuclear leukocytes release a different effector molecule with an m.w. of 55 K that inhibits fibroblast collagen production. Mononuclear leukocytes in culture are capable of releasing both the stimulator and the inhibitor of collagen production. The relative amounts of each of these factors elaborated by mononuclear leukocytes in culture appear to be influenced by several variables, such as cell density, type of stimulant used, and the duration of the culture period. These observations suggest that collagen production by fibroblasts in close proximity to sites in vivo where cell-mediated immune reactions are occurring might be regulated by both of these effector molecules.