The humoral immune response developed by C57BL/6J mice against the beta 2-microglobulin (beta 2m) and major histocompatibility complex (MHC) class I- and class II-deficient cell variant of L5178Y, LR.4, is strain specific, is not linked to a given haplotype and involves at least one antigenic determinant expressed on the cell membrane. Anti-LR.4 antibodies can be detected in the serum and ascitic fluid of tumour-bearing animals, and in the serum of mice immunized with mitomycin C (MC)-treated cells. In vitro, cytotoxic T lymphocytes (CTL) cannot be induced under different experimental conditions. However, recognition and lysis of LR.4 are mediated by an antibody-dependent cell-mediated cytotoxicity (ADCC) mechanism in which natural killer (NK) cells extracted from the spleen of resistant or susceptible strains are the effector cells. The NK cells responsible for ADCC against LR.4 are not inducible with polyinosinic-polycytidylic acid (poly(I:C)) and could represent a subset that is not detectable by conventional assays. In conclusion, the incapacity of BALB/c and possibly of other strains of mice to reject LR.4 is determined by the failure to mount a humoral immune response.