A fitness-fatness index (FFI) was recently (2016) developed, with FFI calculated as cardiorespiratory fitness divided by waist-to-height ratio (HR). No study has evaluated the effects of FFI on cancer-specific mortality risk, which was this study’s purpose. Data from the 1999–2006 National Health and Nutrition Examination Survey were employed, with follow-up through 2011. Among the 9,974 participants, 138 died of cancer over the follow- up period; median follow-up period was 105 months (IQR: 81–129). In a Cox proportional hazard model, for every 1 FFI unit increase, participants had an 8% reduced hazard of cancer-specific death [HR = 0.92; 95% confidence interval (CI): 0.88–0.96; P < 0.001]. Results were unchanged when stratifying by men (HR = 0.90; 95% CI: 0.85–0.94; P < 0.001) or women (HR = 0.86; 95% CI: 0.79–0.93; P = 0.001). Results were also similar for cancer survivors (HR = 0.89; 95% CI: 0.83–0.95; P = 0.001). This novel study presents evidence of an inverse association between FFI on cancer-specific mortality, among those with and without cancer. Thus, the FFI may be a useful tool in the clinical setting to help identify those at high risk of early cancer-specific mortality.