PURPOSE: The aim of this study was to investigate the joint association of systemic inflammatory response index (SIRI) and sarcopenia with cancer-specific and all-cause mortality in individuals with self-reported cancer. METHODS: The study cohort comprised individuals with a self-reported cancer diagnosis from the NHANES database, with data collected between 1999 and 2006 and 2011-2018. The researchers tracked deaths up to 31 December 2019 by linking the relevant records to those held by the (NDI). A weighted sampling design was employed, with participants stratified according to the median value of the SIRI. Cox regression models were employed to assess the association between SIRI, sarcopenia, all-cause mortality, and cancer-specific mortality. RESULTS: The study cohort comprised 1316 individuals with self-reported cancer. Over a median follow-up period of 9.21 years, 523 all-cause deaths were recorded, including 163 cancer-specific and 360 non-cancer deaths. Adjusting for multiple confounders, elevated SIRI levels were significantly associated with increased risks of all-cause (HR = 1.90 [1.58-2.28]), cancer (HR = 1.88 [1.26-2.78]), and non-cancer mortality (HR = 1.93 [1.54-2.41]). Sarcopenia also emerged as a significant predictor of mortality. Individuals with sarcopenia faced a 50% higher risk of all-cause mortality (HR = 1.50 [1.18-1.91]) and a 54% higher risk of non-cancer mortality (HR = 1.54 [1.11-2.12]). However, the association with cancer mortality was not significant in the fully adjusted model. When both sarcopenia and elevated SIRI were present, the risk was the highest for all-cause (HR = 2.54 [1.92-3.37]), cancer (HR = 2.29 [1.19-4.40]), and non-cancer mortality (HR = 2.63 [1.78-3.89]). Elevated SIRI alone was linked to significant risks for all-cause (HR = 1.91 [1.51-2.42]), cancer (HR = 1.95 [1.28-2.97]), and non-cancer mortality (HR = 1.92 [1.46-2.53]). Sarcopenia alone significantly increased the risk of all-cause mortality (HR = 1.63 [1.01-2.56]) but not cancer mortality. CONCLUSION: Our study is the first to demonstrate the joint association between the SIRI and sarcopenia with mortality among individuals with self-reported cancer. These findings underscore the importance of assessing and managing these two factors in individuals with self-reported cancer to reduce the risk of death and improve survival outcomes.