Two different human malignant squamous cell lines (SCL-1 and SW-1271) and normal human foreskin fibroblasts were treated with recombinant human alpha, beta, and gamma interferons. HLA-DR expression was induced in a concentration-dependent fashion only on the SCL-1 cells treated with recombinant human gamma interferon (r-IFN-gamma) (10(2)-10(3) U/ml). No HLA-DR expression was observed with alpha or beta interferon on either malignant squamous cell line, nor with gamma interferon on SW-1271 cells. All three interferons reduced the number of malignant cells growing in culture but had no effect on the fibroblasts. There was a concentration-dependent growth-inhibitory response of the malignant cells by the interferons (dose range 1-10(3) U/ml; 7.1 X 10(-12) M to 7.1 X 10(-9) M). The SCL-1 cells were 10(2) more sensitive (based on weight) to the antiproliferative effects of gamma interferon than alpha or beta interferon. A brief (30-min) exposure of the SCL-1 cells to r-IFN-gamma (10(2) and 10(3) U/ml) produced approximately the same inhibition of cell growth as continuous exposure over a 2-week period. The SW-1271 cells were equally sensitive to alpha, beta, and gamma interferons. However, the maximal inhibitory effect on SW-1271 cells was less than that observed for the SCL-1 cells. Combining beta and gamma interferon resulted in cytotoxicity with SCL-1 cells and additive cytostatic effect on the SW-1271 cells. These additional malignant cell lines with their different sensitivities to alpha, beta, and gamma interferons may prove useful in studying the mechanisms of action of various interferons.