The cytokine TWEAK and its cognate receptor Fn14 are members of the TNF/TNFR Superfamily and are upregulated in tumors. We found that Fn14, when expressed in tumors, causes cachexia, and that antibodies against Fn14 dramatically extended lifespan by inhibiting tumor-induced weight loss while having only moderate inhibitory effects on tumor growth. Anti-Fn14 antibodies prevented tumor-induced inflammation and loss of fat and muscle mass. Fn14 signaling in the tumor, rather than host, is responsible for inducing this cachexia because tumors in Fn14- and TWEAK-deficient hosts developed cachexia that was comparable to that of wild type mice. These results extend the role of Fn14 in wound repair and muscle development to involvement in the aetiology of cachexia and indicate that Fn14 antibodies may be a promising approach to treat cachexia, thereby extending lifespan and improving quality of life for cancer patients.