The immune response of 42 gastrointestinal and ovarian cancer patients at 1 month after exposure to murine monoclonal antibodies (B72.3 and CC49) reactive with the tumor-associated antigen TAG-72 was studied. The incidence of human anti-mouse antibody response was 89% to B72.3 and 70% to CC49. To evaluate the antiidiotypic immune response, we developed a serological assay based on affinity chromatography to remove the interference due to the presence of TAG-72, antiisotypic, and antiallotypic immunoglobulins in the serum. Seventy-eight percent of patients who received B72.3 developed an antiidiotypic response; in 33% of the patients, this was the only immune response detected. The antiidiotypic immune response after treatment with CC49 was present in 54% of the patients. Twelve percent of the patients who received CC49 developed an antiidiotypic response in the absence of antiisotypic or antiallotypic immune response. The lower immunogenicity of the variable region of CC49 is encouraging when considering the use of chimeric or humanized antibodies derived from the murine monoclonal antibody CC49 in clinical studies.