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• Elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, and cancer among middle-aged and elderly Chinese. • The weighted genetic risk score constructed on 18 established Hcy-related genetic variants had significant interaction with Hcy on CHD mortality. • The rs7130284 and rs957140 on NOX4 gene modified the association between Hcy and mortality from CVD and CHD. • The rs154657 on DPEP1 gene modified the association between Hcy and CHD mortality. The associations of homocysteine (Hcy) and gene-Hcy interactions with the risk of all-cause and cause-specific mortality remain unclear. A total of 19,826 middle-aged and elderly Chinese adults were included from the Dongfeng-Tongji cohort in 2013–2014 and were followed-up to 31 December 2018. Cox regression was used to examine the association between Hcy and mortality. We selected 18 well-established Hcy-associated genetic variants to constructed the weighted genetic risk score (GRS) among 15,434 participants with genetic data, and interactions between genetic susceptibility and Hcy on mortality were assessed. After multivariate adjustment, elevated serum Hcy levels were associated with higher risk of mortality from all-cause, CVD, coronary heart disease (CHD), stroke, and cancer. We also observed a significant interaction between GRS and Hcy on CHD mortality. Moreover, the rs7130284 and rs957140 on NOX4 modified the association between Hcy and mortality from CVD and CHD, and rs154657 on DPEP1 modified the association between Hcy and CHD mortality. Elevated Hcy levels were associated with increased risk of all-cause and cause-specific mortality among middle-aged and elderly Chinese. Hcy-related genetic variants on NOX4 and DPEP1 might modify the associations of Hcy with CVD mortality or CHD mortality. [ABSTRACT FROM AUTHOR]