Ethanol consumption results in significant changes in the immune system of experimental animals and humans. Previous work by ourselves and others has established that in utero exposure to ethanol results in alterations in the immune system of the offspring that persist into adult life. The present study was designed to determine if prenatal exposure to ethanol results in increased vulnerability to the immunosuppressive effects of ethanol consumption in adulthood. Male and female Sprague-Dawley offspring were selected in adulthood from prenatal ethanol (E), pair-fed (PF), and ad libitum-fed control (C) groups, and given either an ethanol-containing liquid diet or were pair-fed an isocaloric liquid diet without ethanol for 30 days. At the end of the 30-day feeding period, lymphocyte responses to the mitogens concanavalin A (Con A) and lipopolysaccharide, and to interleukin-2 (IL-2) were tested using in vitro assays. The results of this study support and extend previous data demonstrating long-term adverse effects of prenatal ethanol exposure on T-cell responses to mitogens, and provide further evidence that deficits seem to be more robust in male than in female offspring. Prenatal E males showed reduced T-lymphocyte proliferation to Con A and T-lymphoblast proliferation to IL-2, compared with their prenatal PF and C counterparts, regardless of whether they were exposed to the ethanol or the control diet in adulthood. In addition, T-lymphoblast proliferation to IL-2 was suppressed in prenatal E, compared with prenatal C, females exposed to control diet in adulthood. This is the first report of a deficit in T-cell aspects of immunity in E females, although it appears that this deficit may have been partially mediated by nutritional effects. A second major finding in this study is that consumption of ethanol diet in adulthood in itself had significant immunosuppressive effects on T-cell responses in both males and females. However, contrary to our expectation, previous exposure to ethanol in utero did not exacerbate the changes in immune responsiveness that were observed after adult ethanol consumption.