To investigate whether human melanoma cells intrinsically resistant to autologous LAKs do exist, and whether a relationship between the level of lysis of LAKs and spontaneous drug resistance can be identified at the clonal level, we studied 44 clones obtained from a metastatic melanoma lesion. The antigenic phenotype of clones revealed a marked heterogeneity in the expression of HLA antigens of classes I and II. The clones were subsequently tested for sensitivity to autologous LAK and for spontaneous resistance to Dx. No clone resistant to autologous LAK was found, although a considerable range of lysis was noted with a normal frequency distribution. Growth in agar of the 2 clones in which lysis was least pronounced (6 and 26) was completely inhibited after co-culture with LAKs, indicating a lack of absolute resistance to these effectors. Spontaneous resistance to Dx, evaluated as ID50, revealed instead that the majority of clones had a low ID50. The frequency distribution of clones showed a left-skewed curve. The percentage of specific 51Cr-release and the ID50 for Dx could be correlated in 25 clones by linear regression. Sensitivity to LAK did not correlate with HLA classes I or II or melanoma-associated antigen expression. These results support the contention that increased LAK sensitivity of tumor cells is associated with drug resistance.