Since maternal-fetal immunogenetic disparity facilitates growth of the fetoplacental unit, nonspecific depression of the maternal immune system by immunosuppressive drugs could result in previously unrecognized adverse effects such as fetal growth retardation. To test this hypothesis, groups of 6 to 8 primigravid Fischer female rats mated with DA or Fischer male rats were treated with saline (controls) or either cyclophosphamide (Cytoxan) or azathioprine (Imuran) in doses similar to those used therapeutically in human subjects. It was found that these drugs caused an increased incidence of fetal death and produced fetal and neonatal growth retardation. Smaller placentas and fetuses reflected a decrease in cell number rather than cell size whereas water, fat, and protein content were only minimally affected. Analyses of mean maternal weight gain, spleen weight assays, and changes in the lymph nodes draining the uterus indicate that effects detrimental to the offspring are primarily the result of immunologic and cytotoxic mechanisms. Moreover, a review of the literature suggests that these immunosuppressive agents are also associated with small-for-gestational age infants in human pregnancies.