The restoration of normal bone remodeling in osteopetrotic animals by transplantation of spleen or bone marrow cells from normal littermates has suggested that the connective tissue abnormalities associated with this disease may be attributed to defective functions of the cells of the immune system. Examination of several immunologic parameters has revealed that both thymocytes and macrophages from osteopetrotic (op) rats express some dysfunctions but retain other activities. Mitogen-induced proliferation of thymocytes from affected rats is significantly lower than that of thymocytes from normal littermates. However, mitogen-activated thymocytes from op rats produce levels of a chemotactic lymphokine that are similar to those produced by the thymocytes from normal animals. Peritoneal exudate macrophages from op rats are defective in that they migrate minimally in response to a chemotactic lymphokine or C5a. These macrophages do, however, produce lymphocyte-activating factor as efficiently as those from the unaffected littermates. The results presented here, which document immunologic defects in the lymphocytes and macrophages from the op rat, indicate that multiple immunoregulatory mechanisms involved in the degradation of connective tissue may contribute to the skeletal malformations that are present in this animal model.