Extract: Specific antibody production by spleen cells of male and female mice during a noninvasive enteric infection with Escherichia coli and after parenteral injection of heat-killed E. coli was studied by use of the Jerne-Nordin agar plaque technique. Following experimental enteric colonization with E. coli 0127 significantly greater proportions of spleen cells produced specific anti-0 antibody in immature weanling female mice than in their male littermates. Anti-E, coli 0127 plaque-forming cells were also found in significantly greater numbers in the spleens of immature females than in males following intraperitoneal injection of small numbers of heat-killed E. coli. Although many spleens from male mice produced no cell plaques after a small dose of antigen, responses by the sexes were comparable after injection of large numbers of heat-killed bacteria.Production of plaques by spleen cells from female animals after injection of small amounts of antigen increased significantly with age, but the responses observed in adult male mice were only slightly and insignificantly greater than those of male weanlings. Studies of the sizes of plaques produced by spleen cells of male and female animals showed no statistical differences. Young ovariectomized females responded in the same way as their sham-operated male littermates to small amounts of E. coli antigen. Administration of small doses of estrogen increased plaque formation by spleen cells of weanling males.It appears that an effect of female sex hormones is production of greater numbers of antibody-producing cells; yet in the final phase of antibody production, individual cells from each sex produce on the average the same amounts of antibody.Speculation: The better ability of the immature female to respond immunologically to a small amount of E. coli 0 antigen may be a significant factor in her superior resistance to invasive disease with E. coli. Differences in the immune response of the two sexes appear to occur in the proliferative phase of antibody-producing process or steps leading up to this phase, but not in the final phases of antibody production by the cell. By mechanisms not yet defined, estrogen appears to enhance the proliferation of immunocompetent cells, and secretion of estrogen by the female may explain her superior immunologic responsiveness.