ObjectiveInvestigating the associations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) with all-cause, cardiovascular disease (CVD) and cancer mortality in a large cohort of community-dwelling patients with type 2 diabetes mellitus (T2DM).DesignCommunity-based prospective cohort study conducted between 2013 and 2014.Setting44 selected townships in Changshu and Huai’an City, Jiangsu province, China.Participants20340 participants with T2DM were recruited in Jiangsu province, China.MethodsWe use Cox proportional hazard models to estimate the HR and 95% CIs of associations of serum ALT and AST levels with all-cause and cause-specific mortality. Restricted cubic splines were used to explore the dose-response relationships between ALT and AST levels with mortality.ResultsALT and AST levels were inversely associated with CVD mortality, compared with the lowest quintile (Q1), the multivariable HRs of the highest quintile (Q5) was 0.82 (95% CI: 0.66 to 1.01, p for trend=0.022) and 0.78 (95% CI: 0.63 to 0.96, p for trend=0.022), respectively. Furthermore, the HRs for ALT levels in all-cause mortality were 0.90 (95% CI: 0.79 to 1.01, p for trend=0.018), and the HRs for AST levels in cancer mortality were 1.29 (95% CI: 1.02 to 1.63, p for trend=0.023). Stronger inverse effects of ALT and AST levels on all-cause mortality were observed in the older subgroup and in those with dyslipidaemia (all p for interaction <0.05). Further analysis based on gender showed that the associations between serum aminotransferases and the mortality risk were more significant in women and substantially attenuated in men.ConclusionOur findings suggested patients with T2DM with lower levels of ALT and AST had an increased risk of CVD mortality, which needs confirmation in future clinical trials.