Peripheral blood lymphocytes and tumor cells were obtained from 31 patients with giant cell tumors of bone and cocultured in vitro in a mixed lymphocyte tumor cell assay. The lymphocyte proliferative response was measured by incorporation of 3H thymidine. Also, the patients' lymphocytes were tested for proliferative reactivity to phytohemagglutinin and allogenic lymphocytes to evaluate nontumor immunologic competence. Mixed lymphocyte tumor cell assays showed higher lymphocyte stimulation in patients with Stage I as compared with Stages II and III giant cell tumors. The proliferative response was blocked partially when the patients' sera was used to supplement the cultures. Lymphocytes from patients with a recurring tumor showed lower responses, but the differences with primary tumors were not significant. This evidence suggests that there is an immune response to giant cell tumor antigens and that this response might be related to the aggressiveness of the tumor.