Lewis lung carcinoma (LLC)-bearing mice were used as a mouse model to evaluate effects of recombinant human (rh) interleukin (IL) 6 and local X-irradiation (LR) on the growth of primary tumors and lung metastases. Mice were inoculated s.c. with LLC tumor cells and then treated with rhIL-6 (100 ng/dose) s.c. twice a day (b.i.d.) for 5 days, beginning 6 days after tumor inoculation. LR (800 cGy) was administered to the site of the primary tumor 6 days after tumor inoculation and again 1 wk later. Mice were then observed for survival or sacrificed at day 21 after tumor inoculation to determine size of primary tumor, numbers and size of lung metastases, and other hematological parameters including numbers of granulocyte-macrophage progenitor cells (CFU-gm). The size of the primary tumor and numbers of lung metastases were reduced by rhIL-6. LR enhanced the antitumor effect of rhIL-6 significantly, while LR alone had only a slight antitumor effect. Tumor-associated increases in peripheral blood, femoral marrow, splenic-nucleated cellularity, and marrow and splenic CFU-gm were reduced in mice treated with rhIL-6 plus LR. Prolonged survival time was observed only in tumor-bearing mice treated with rhIL-6 in combination with LR. The antitumor effects in vivo of rhIL-6 appear to be mediated indirectly as rhIL-6 had no effect on proliferation of LLC cells in vitro as assessed by colony and 3H-thymidine incorporation assays. These studies suggest that rhIL-6 may have therapeutic value in the treatment of certain malignancies, especially if used in combination with LR.