Nude mice were inoculated with CHOIIFN-y cells, a line of Chinese hamster ovary tumor cells, that had been genetically engineered to produce murine IFN-y. Severe cachexia, as evident from body weight loss and reduced food intake, occurred in these mice, but not in those injected with CHOI control cells, Le. the original, non-IFN-y-producing line. The essential role of IFN-y in the pathogenesis of cachexia was confirmed by the demonstration that monoclonal antibodies (MAbs) against IFNy, given prior to injection of the tumor cells, prevented cachexia. In addition to IFN-y, the presence of the tumor cells was also required for cachexia to develop. As evident from pair-feeding experiments, reduced food intake could only partially account for the rapid and extensive body-weight loss. Cachexia was characterized by a marked reduction in the amount of interscapular fat tissue. Injected tumor cells exclusively invaded intraperitoneal adipose tissue and elicited an inflammatory cell infiltrate, indicating that interscapular fat loss was due to humoral factors. Our data suggest that, among the humoral factors responsible for cancer-associated cachexia, IFN-y plays a prominent role.