The toxicity and therapeutic efficacy of the combination of recombinant interferon gamma (rIFN-gamma) and alpha (rIFN-alpha) was investigated in 15 patients with metastatic melanoma. Patients were treated with an escalating dose of rIFN-gamma and a fixed dose of rIFN-alpha administered s.c. 3 times a week. The maximum dose was well tolerated. The median survival time of the patients was 7 months; no clinical remissions were observed. In the majority of cases, expression of HLA class-I and -II antigens on the patients' peripheral blood lymphocytes and monocytes increased markedly during treatment. An increase in HLA-DR expression of peripheral blood T lymphocytes was correlated with a longer survival time. This suggests that activation of T lymphocytes may have a favourable influence on the course of metastatic disease. The in vitro anti-proliferative activity of IFNs on melanoma cell lines isolated from melanoma metastases during treatment of 3 patients was determined. In contrast to the lack of in vivo anti-tumour effect in patients, both rIFN-gamma and rIFN-alpha inhibited DNA synthesis of these melanoma cell lines in vitro, combined IFNs acting synergistically. Anti-proliferative activity observed in vitro occurred at IFN concentrations below the peak serum levels achieved in vivo.