Accelerated fibroblast accumulation, mitosis, and deposition of collagen during fibrotic processes are frequently preceded by intense inflammatory exudates of mononuclear cells which are derived from the peripheral blood. In vitro, we examined the role of human peripheral blood mononuclear cells in activation of human fibroblasts. The adherent mononuclear phagocyte, or monocyte, was found to release mediators which stimulate fibroblast proliferation and enhance collagen production. Adherence to tissue culture dishes in vitro was found to activate the release of these monocyte products, and represents a process which mimics in vivo extravasation of monocytes from the blood vessel into the connective tissue. The release of these mediators is dependent on monocyte protein synthesis, metabolism, and protease activity. Little is known of the role that immunologic sensitization to autologous connective tissue components might play in inducing such inflammatory responses which can result in pathologic fibrotic sequelae. In beginning to explore these possibilities, we have found that levels of antibodies to types I (interstitial) and IV (basement membrane) collagen correlate directly with the extent of pulmonary fibrosis in patients with scleroderma. Furthermore, we can sensitize mice to homologous types I or IV collagen, or laminin (a basement membrane attachment protein), and elicit a delayed type hypersensitivity response which is marked by mononuclear cell infiltration. Cell-mediated immunity to these antigens can be transferred to normal recipients with sensitized T-lymphocytes. We discuss these data and propose a hypothesis for mechanisms of monocyte extravasation → fibroblast activation → fibrosis.