Sequential tumor biopsies from 9 patients with disseminated cancers were obtained before, during, and after treatment with interleukin-2 (IL-2) with or without the adoptive transfer of lymphokine-activated killer (LAK) cells. Infiltrating lymphoid and tumor cells were characterized in frozen sections by the use of monoclonal antibodies and the avidin-biotin complex (ABC) immunoperoxidase technique. Five patients had objective tumor regression (1 complete response of a follicular lymphoma, 4 partial responses of melanomas). Four patients (2 melanomas, 1 renal cell carcinoma, 1 breast carcinoma) were nonresponsive after treatment. After treatment, responsive tumors showed a pronounced infiltration of T cells, mainly Leu-2+ (CD8, primarily cytotoxic/suppressor) cells. Macrophages, although increased, were fewer than the T cells, and Leu-7+ or Leu-11+ (NK and K) cells were virtually absent. In nonresponders, there was no significant increase in lymphoid cells after therapy, and no differences were noted between groups before therapy. In 4 of 5 responders, tumor cells were positive for HLA-DR before therapy; and in the remaining responder, the tumor became positive during treatment. Tumor cells in all biopsy specimens from nonresponders were DR- before and after the start of therapy. It is concluded that the expression of HLA-DR by tumor cells may play a role in the response to IL-2 with or without LAK and that marked infiltration by T cells accompanies, and possibly mediates, such a response.