The immunosuppression exhibited by a water-soluble condensate of tobacco smoke (WSC) has been studied in vivo and in vitro. When multiple sublethal doses of WSC were injected into C57Bl/6 mice, their ability to respond to immunization with sheep erythrocytes by the formation of plaque-forming cells was severely inhibited. In addition, spleen cells from WSC-treated mice were unable to mount a primary response to SRBC in vitro. Studies on the cellular basis of the immunosuppression induced by WSC showed a decrease in T lymphocytes in the spleens of WSC-treated mice. Additional experiments were conducted in which isolated populations of T cells, B cells and macrophages from WSC-treated or normal mice were combined and then tested for responsiveness to SRBC in vitro. Results of these experiments also indicated that T cells were particularly susceptible to WSC exposure. T cells from WSC-treated mice were unable to co-operate with normal B cells and macrophages in the response to SRBC. A less marked suppression of B-cell function was noted in condensate-treated mice. While B cells from such animals were able to co-operate with normal T cells and macrophages to give a detectable primary response to SRBC, the response was depressed. In contrast, macrophages from WSC-treated animals enhanced the response of normal T and B cells to SRBC.