BackgroundInflammation can increase vitamin B6 uptake and catabolism. Higher vitamin B6 turnover [4-pyridoxic acid (4-PA)/pyridoxal 5'-phosphate (PLP) ratio], was associated with mortality risk in the general population. ObjectivesWe aimed to investigate the association between 4-PA/PLP and long-term mortality in patients with type 2 diabetes mellitus (T2DM), an inflammatory disease. MethodsIn this prospective cohort study from the National Health and Nutrition Examination Survey (NHANES) cycles 2005–2010, the concentrations of 4-PA and PLP in plasma were measured using high-performance liquid chromatography, with mortality data updated to 31 December 2019. We included 2074 patients with T2DM aged between 20 and 85 y at baseline. ResultsThere were 739 deaths among 2279 patients with T2DM with a median follow-up of 11.83 y. In the age- and sex-adjusted COX model (model 1), 4-PA/PLP was positively associated with mortality in patients with T2DM [hazard ratio (HR) and 95% confidence interval (CI) highest compared with lowest quartiles: 35.55 (18.29, 69.09); P < 0.001], and in model 3, which was adjusted for demographics as well as inflammation, nutrition, and renal function, high 4-PA/PLP concentrations remained an independent risk factor for mortality in patients with T2DM [HR (95% CI) highest compared with lowest quartiles: 5.03 (2.46, 10.30); P < 0.001]. In restricted cubic spline (RCS), the link between 4-PA/PLP and all-cause mortality displays a positive correlation. Patients with died within the previous 2 y were excluded, the sensitivity analysis had no effect on the association between 4-PA/PLP and mortality in patients with T2DM. Finally, comparable results were found in subgroup analyses of specific-cause mortality. ConclusionHigher vitamin B6 turnover is associated with long-term mortality risk in patients with T2DM. 4-PA/PLP may serve as a convenient prognostic marker in T2DM management.