In mice, infection with Leishmania tropica initially produced a nonspecific enhancement of the immune response to sheep erythrocytes as measured both in vitro and in vivo. Subsequently, the spleen cell responses of susceptible mice (BALB/c) to sheep erythrocytes and T- and B-cell mitogens in vitro decreased dramatically, whereas those of the resistant strain (C57BL/6) returned to normal. Analysis of the spleen cells of infected animals revealed that macrophages (the target cells of Leishmania) were not defective. However, both T- and B-cell-depleted splenocyte populations of infected animals lacked the ability to respond in the presence of their corresponding B- and T-cell-depleted populations of normal spleen cells. It was also observed that the addition of various numbers of Leishmania organisms did not alter the response of normal spleen cells in vitro. The results of cocultures of various ratios of cells from the spleen of infected and normal animals ruled out the possibility of a strong active immunosuppression. The decrease of in vitro response is attributed to the depletion of immunocompetent cells in the spleen of infected mice, which is heavily populated by null cells.