We have shown previously that interleukin-2 (IL-2) and the interferon inducer ABPP can induce lymphokine activated killer (LAK) cell activity in vivo after intraperitoneal (i.p.) administration. The antitumor effects of various immunotherapy regimens with IL-2, LAK cells, ABPP, and cyclophosphamide (CY) on microscopic (day 3) and on macroscopic (day 8) i.p. tumors, differing in histology and immunogenicity, were studied in C57BL6 mice. The immunogenic sarcomas MCA-105, -106, and the colon adenocarcinoma MCA-38, and the nonimmunogenic sarcomas MCA-101, -102 were used. After i.p. inoculation of 1 X 10(5) tumor cells i.p. on day 0, therapy with IL-2 +/- LAK cells consisted of 1 X 10(8) LAK cells, i.p., on day 3 and IL-2, 10k to 25k U, i.p., b.i.d., on days 3 to 7. Treatment with ABPP +/- CY consisted of CY, 50 mg/kg, i.p., on day 3 and/or 8 ABPP, 250 mg/kg on days 3, 4 and/or 8, 9. In the treatment of micrometastases, IL-2 + LAK cell therapy was effective against all tumors. Therapy with low dose IL-2 alone was effective only against immunogenic tumors. Combined therapy with CY was very effective against the immunogenic tumors and prolonged survival significantly. Only marginal antitumor effects were seen against nonimmunogenic tumors. In the setting of advanced tumor, chemoimmunotherapy was only successful against immunogenic tumors. These observations demonstrate that the immunogenicity of the tumor is of major importance in the outcome of immunotherapy, especially in the setting of advanced disease. This indicates that, apart from LAK cells, the in vivo activation of other cytotoxic effector cells is important in the rejection of immunogenic tumors.