Saccharin is a widely used sugar substitute, but little is known about the long-term health effects of saccharin intake. Our study aimed to examine the association between saccharin intake and mortality in diabetic and pre-diabetic population and overweight population from NHANES 1988-1994. Cox proportional hazard models were used to evaluate the association between saccharin intake and CVD, cancer and all-cause mortality. After multivariable adjustment, increased absolute saccharin intake was associated with the risk of all-cause mortality (hazard ratio (HR): 1·41, 95 % CI: 1·05, 1·90), CVD mortality (HR: 1·93, 95 % CI: 1·15, 3·25) and cancer mortality (HR: 2·26, 95 % CI: 1·10, 4·45) in diabetic and pre-diabetic population. Among overweight population, higher absolute saccharin intake was associated with the risk of cancer mortality (HR: 7·369, 95 % CI: 2·122, 25·592). Replacing absolute saccharin intake with total sugar significantly reduced all-cause mortality by 12·5 % and CVD mortality by 49·7 % in an equivalent substitution analysis in the diabetic and pre-diabetic population. Aspartame substitution reduced all-cause mortality by 29·2 % and cancer mortality by 30·2 %. Notably, the relative daily intake of saccharin also had similar effects as the absolute intake on all-cause, cardiovascular and cancer mortality in all analyses. This was despite the fact that the relative daily intake in our study was below the Food and Drug Administration limit of 15 mg/kg. In conclusion, our study showed a considerable risk of increased saccharin intake on the all-cause, CVD mortality and cancer mortality.