RAS oncogene expression has been reported to affect several biological features of rodent tumour cells, including lysability by activated natural killer cells. In order to examine whether expression of mutated RAS genes in human melanoma cells alters their susceptibility to lysis by LAK cells, seven melanoma lines were assessed for the presence of Ki- and NRAS genes bearing all possible mutations at codons 12,13 and 61. A panel of 21 clones deriving from the metastic lesion Me665/2, which had a Gin -> Arg substitution at codon 61 of NRAS (N-RAS/61+), were also examined. Melanoma cells and clones were used as targets of allogeneic LAK in a 4-h 51Crrelease assay. LAK showed a higher lysis on melanoma lines and clones harbouring a mutated RAS compared with counterparts bearing no RAS mutations. In addition, LAK-mediated lysis drastically decreased on Me665/2 sublines progressively selected by exposure to LAK. This loss was paralleled by a reduction or even disappearance of N-RAS/61+ mRNA signal in Me665/2 sublines. To evaluate whether N-RAS could directly modulate LAK susceptibility to lysis, N-RAS/61+ gene was transfected in two N-RAS wild type (N-RAS/61-) 665/2 melanoma clones by a cosmid vector. In contrast to the high lysability of melanoma cells constitutively expressing the mutationally active N-RAS oncogene, N-RAS/61+ transfectants did not show a consistent high lysability by LAK, compared with some control pSV2neo transfectants. Taken together, these results indicate that expression of a mutated RAS gene can be considered as a factor, although not the only one, that characterizes human melanoma cells with high susceptibility to lysis and may thus affect their response to therapeutic lymphocytes.