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Background: This study explored the association of cardiovascular disease (CVD) with cancer mortality risk in individuals with or without a history of cancer, to better understand the interplay between CVD and cancer outcomes. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) spanning 1999 to 2018, a retrospective cohort analysis was conducted. This analysis accounted for the survey's complex design to ensure national representativeness. The association of CVD with cancer mortality was assessed through multivariable Cox proportional hazards models. Results: The present study included 59,653 participants, of whom 54,095 did not have cancer and 5558 had a history of cancer. In individuals without cancer, heart failure (HF) was associated with an increased risk of mortality from cancer (HR, 1.36; 95% CI, 1.09–1.69; P = 0.005). In participants with cancer, HF correlated with a higher risk of mortality from cancer (HR, 1.76; 95% CI, 1.32–2.34; P < 0.001). Diabetes (DM), hypertension (HBP) and coronary heart disease (CHD) were not significantly associated with an increased risk of mortality from cancer. Significant differences were observed in the interaction between cancer and CHD (HR, 0.68; 95% CI, 0.53–0.87; P = 0.002). For cancer and HBP, a similar trend was noted (HR, 0.75; 95% CI, 0.62–0.91; P = 0.003). No significant differences were found in interactions between HF, DM and cancer. Conclusions: HF was associated with an increased risk of mortality from cancer, regardless of cancer history, while HBP, CHD and DM showed no significant association. These findings underscore the importance of understanding the mechanisms behind the increased risk of cancer mortality following HF. [ABSTRACT FROM AUTHOR]