In vivo administration of Ly-6 mAb which recognize lymphoid differentiation Ag encoded for by the Ly-6 gene complex were found to have significant beneficial immunotherapeutic effects in tumor-bearing mice. The effectiveness of the mAb treatment in mice bearing sarcomas, leukemias, or melanomas was dependent on the host and not the tumor Ly-6 phenotype. The treatment was effective in nu/nu mice, although a more pronounced inhibition of tumor growth occurred in immunocompetent mice. The effectiveness of the therapy in immunocompetent mice was dependent on the dose of mAb and was influenced by the immunogenicity of the tumor. It ranged from significant growth inhibition of weakly immunogenic tumors to complete rejection of strongly immunogenic tumors. The results of cell-mediated cytotoxic assays of splenocytes from mAb-treated mice indicated that Ly-6 mAb treatment induced and/or augmented tumor-specific CTL as well as NK cell activity in these mice. Ly-6 mAb treatment represents a novel method for tumor immunotherapy using mAb recognizing lymphoid differentiation Ag with functional activities.