The murine IgG3 monoclonal antibody NCC-ST-421 (ST-421), raised against human gastric cancer, shows strong reactivity with the Le(a)/Le(a) (al-fucosylated extended type 1 chain) antigen expressed on gastrointestinal (GI) cancer cells. ST-421 is capable of mediating both antibody-dependent cellular cytotoxicity (ADCC) by human peripheral blood lymphocytes (PBL), and complement dependent cytotoxicity (CDC). We investigated combination immunotherapy with OK-432, a streptococcal preparation, and ST-421 in vitro and in vivo. ADCC against Colo 205 (a human colon cancer cell line) was enhanced 2 to 3 fold after preincubation of PBL with OK-432 in vitro. These effect's were strongest when PBL were preincubated with OK-432 at a concentration of 0.5 ng/ml for 24 hours. In vivo, a human colon cancer xenograft model exhibited significant growth suppression after combined treatment with ST-421 and OK-432. Such combination immunotherapy may therefore be clinically useful in GI cancer.