Background: Whether the dynamic weight change is an independent risk factor for mortality remains controversial. This study aimed to examine the association between weight change and risk of all-cause and cause-specific mortality based on the Linxian Nutrition Intervention Trial (NIT) cohort.Methods: Body weight of 21,028 healthy residents of Linxian, Henan province, aged 40-69 years was measured two times from 1986 to 1991. Outcome events were prospectively collected up to 2016. Weight maintenance group (weight change <2 kg) or stable normal weight group was treated as the reference. Cox proportional hazard model was performed to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs) to estimate the risk of mortality.Results: A total of 21,028 subjects were included in the final analysis. Compared with the weight maintenance group, subjects with weight loss ≥2 kg had an increased risk of death from all-cause (HRAll-cause = 1.14, 95% CI: 1.09-1.19,P <0.001), cancer (HRCancer = 1.12, 95% CI: 1.03-1.21,P = 0.009), and heart disease (HRHeart diseases = 1.21, 95% CI: 1.11-1.31,P <0.001), whereas subjects with weight gain ≥5 kg had 11% (HRCancer = 0.89, 95% CI: 0.79-0.99,P = 0.033) lower risk of cancer mortality and 23% higher risk of stroke mortality (HRStroke = 1.23,95% CI: 1.12-1.34,P <0.001). For the change of weight status, both going from overweight to normal weight and becoming underweight within 5 years could increase the risk of total death (HROverweight to normal = 1.18, 95% CI: 1.09-1.27; HRBecoming underweight = 1.35, 95% CI: 1.25-1.46) and cancer death (HROverweight to normal = 1.20, 95% CI: 1.04-1.39; HRBecoming underweight = 1.44, 95% CI: 1.24-1.67), while stable overweight could increase the risk of total death (HRStable overweight = 1.11, 95% CI: 1.05-1.17) and death from stroke (HRStable overweight = 1.44, 95% CI: 1.33-1.56). Interaction effects were observed between age and weight change on cancer mortality, as well as between baseline BMI and weight change on all-cause, heart disease, and stroke mortality (allPinteraction <0.01).Conclusions: Weight loss was associated with an increased risk of all-cause, cancer, and heart disease mortality, whereas excessive weight gain and stable overweight were associated with a higher risk of stroke mortality. Efforts of weight management should be taken to improve health status.Trial registration: https://classic.clinicaltrials.gov/, NCT00342654.