Under most experimental circumstances, mice fed a protein antigen produce a smaller serum antibody response than the response elicited in mice that are parenterally immunized with that same antigen. In our experiments, mice fed keyhole limpet hemocyanin or herpes simplex virus type 1 had low, if any, serum IgG antibody responses regardless of whether antigen consumption was voluntary (in drinking fluids) or involuntary (force-fed by pipette). However, when force-feeding occurred during CO2 anesthesia, mice produced significantly higher serum antibody responses, which were comparable to those elicited in mice injected intraperitoneally with the same antigen. Although its mechanism of action is unclear, this potentiating effect does not appear to be mediated by possible CO2-mediated entry of the antigens into the respiratory tract, since mice fed antigen immediately before CO2 anesthesia also had a substantial antibody response.