Three cell lines of small cell lung cancer (SCLC), which were established from specimens of untreated primary tumors biopsied by diagnostic bronchofiberscopy, were analyzed for immunological characteristics. These cell lines showed considerable heterogeneity in chemo-radiosensitivity, which was well correlated with clinical responses of the respective tumors, but their HLA-class I antigen expressions were equally depressed and they were susceptible to peripheral blood lymphocytes (PBL) and lymphokine-activated killer (LAK) cells, irrespective of their diverse chemo-radiosensitivity. Treatment of the cell lines with recombinant immune interferon (rIFN-gamma) increased their HLA-class I antigen expression and conversely depressed PBL sensitivity but not LAK sensitivity. This inverse relationship between HLA-class I expression and PBL susceptibility was also demonstrated using other pairs of autologous PBL and SCLC cell lines. rIFN-gamma changed neither HLA-class II antigen nor SCLC-specific antigen expression under the same experimental conditions. In vitro immunization of allogeneic peripheral blood lymphocytes with rIFN-gamma-treated SCLC cells induced allo-specific killer cells which lysed rIFN-gamma-treated more strongly than non-treated SCLC cells. These results suggest that reduced HLA-class I antigen expression of SCLC could protect the cancer from attack of killer T cells in spite of the higher sensitivity to PBL or LAK cells.