Some cellular immune responses initiate the coagulation protease cascade and promote the formation of fibrin. Local fibrin deposition is requisite for the induration associated with delayed hypersensitivity reactions. The deposited fibrin also is catabolized. In the present study we demonstrate that plasmic cleavage of fibrinogen results in the generation of immunosuppressive activity in vitro that is not expressed by the intact molecule. This property is associated with small dialyzable peptides recovered from advanced plasmic digests of fibrinogen. The peptides inhibit phytohemagglutinin-, pokeweed mitogen-, and allogeneic cell-stimulated blastogenesis as well as proliferation in a dose-dependent fashion. The suppression of lymphocyte responses does not result from loss of cells or their viability. Suppression requires the presence of the peptides at the time of, or immediately after, the exposure of cells to the appropriate stimulus, and is manifest as both a delay and an absolute inhibition of [3H]thymidine uptake. Human peptides inhibit the response of murine spleen cells to mitogens, and B and T lymphocyte classes appear to be equally sensitive to suppression. Thymidine uptake by two continuous lymphoblastoid cell lines also is inhibited by the peptides, indicating a direct effect of the fibrinogen-derived peptides on lymphocytes. In contrast, the peptides stimulate thymidine uptake by a diploid fibroblast line, suggesting selectivity in the biologic effects of the peptides. These observations indicate that in addition to its primary role in hemostasis, the participation of fibrinogen and its derivative fibrin in inflammatory lesions includes the release of lymphocyte-suppressive peptides. This may play a role in regulation of the evolution of immunologic lesions in vivo.