Tamoxifen (TX) and toremifene (TO) enhanced the lysis of P815 mastocytoma cells in vitro by syngeneic DBA2 spleen cells that have been activated by human recombinant interleukin-2 (IL-2) for 6 days (lymphokine-activated killer [LAK] cells). Similarly, enhanced tumor suppression occurred when TX- or TO-treated P815 cells were mixed with LAK cells and injected s.c. into normal DBA2 recipients. Tumor suppression could be increased further by treating such recipients orally with TX or TO and by the repeated injections of LAK cells into the tumor site. The treatment of animals bearing tumors (5 mm in diameter) orally with TX or TO or with LAK cells i.p. resulted in tumor suppression. When the drug treatment was combined with LAK cells, tumor suppression was more pronounced, and complete tumor regression was induced in a significant number of the animals so treated. Our results indicate that the immunotherapeutic effect of LAK cells can be significantly amplified by combined treatment with the anti-estrogens TX or TO.