A hypothesis concerning the mechanism whereby chloroquine phosphate and hydroxychloroquine sulfate are therapeutically active in rheumatoid arthritis is presented, based on in vitro data that (1) utilize drug concentrations not higher than those clinically achievable, and (2) might explain mechanisms that may be applicable in treated rheumatoid arthritis patients. Simple assay systems were used: normal human peripheral blood mononuclear cells were cultured, stimulated with various nonspecific agents, and assayed either for induction of T cell proliferation or generation of immunoglobulin-secreting cells. Results indicate that chloroquine inhibits tritiated thymidine in a dose-dependent way by interfering with the accessory function of monocytes, and that chloroquine inhibits the generation of immunoglobulin-secreting cells by selectively interfering with the secretion of Interleukin 1 by monocytes.