It is well recognized that alcohol passes through the placenta and affects the fetal immune system. The underlying mechanism accounting for immune suppression is not clear. Cytokines are recognized as the principal mediators of a variety of immunologic and pathophysiologic events. The study was designed to examine whether alcohol use during pregnancy affects cytokine synthesis and secretion in the human fetus. Fetal (cord blood) and mother's blood were used for the study. Studies were conducted in vivo and in vitro. For the in vivo study, cytokine levels were measured in cord blood in mothers who drank moderate to heavy (chronic) amounts of alcohol during pregnancy. For the in vitro study, cord blood was obtained from mothers who were drug-free throughout pregnancy. Lymphocytes were isolated and stimulated with lipopolysaccharide (LPS; Escherichia coli, 26:B6). The capacity of lymphocytes to synthesize cytokines was examined in the presence of 20, 50, and 100 mM alcohol. Among the cytokines examined were the tumor necrosis factor (TNF alpha) and interleukins (IL-1 alpha and beta and IL-6). The selection of cytokines was based on their presumptive role in the pathophysiology of alcoholism. Cytokines were measured by using a specific immunoassay. When data obtained from moderate alcohol users were compared with those obtained from nonusers, no significant differences were observed in any of the cytokines examined (p>0.05). In chronic alcohol users, levels for all cytokines increased significantly (p<0.001) in both the fetus and the mother. Among the cytokines, IL-1beta, IL-6, and TNFalpha were the predominant cytokines affected by chronic use of alcohol during pregnancy. The order of stimulation was IL-6, IL-1 beta, TNFalpha, and IL-1 alpha in descending order. In the in vitro study, alcohol blunted LPS stimulation of cytokines, and the alcohol-induced decrease in cytokine synthesis was proportional to the level of alcohol in the media, suggesting a direct effect of alcohol on cytokine synthesis. In general, the blunting effect of alcohol on LPS stimulation was more prominent in the fetus compared with that in mother. We conclude that chronic alcohol use during pregnancy stimulated the fetal cytokine synthesis and secretion, and IL-1beta, IL-6, and TNF alpha were the predominant cytokines affected by alcohol. The in vitro data suggest a direct effect of alcohol on cytokine synthesis.