INTRODUCTION:We examined multiple dietary patterns in relation to total digestive system cancer (DSC) incidence and death.METHODS:A total of 213,038 health professionals from the Health Professionals Follow-up Study (1986–2016), the Nurses' Health Study (1986–2018), and the Nurses' Health Study II (1991–2017) with no cancer diagnosis at baseline were analyzed. DSC incidence and death were estimated using time-varying Cox proportional hazards regression models.RESULTS:During up to 32 years of follow-up, 5,724 DSC cases accrued. Adherence to 8 healthy diet patterns was associated with a 7%–13% lower risk of DSC, particularly for digestive tract cancers. An inverse association with gastrointestinal tract cancer was also shown for all pattern scores except Alternate Mediterranean Diet and the healthful Plant-based Diet Index, with hazard ratios between 0.84 and 0.89. Inverse associations were shown for the reversed empirical dietary index for hyperinsulinemia (hazard ratio for 90th vs 10th percentile 0.64, 95% confidence interval [CI] 0.47–0.87) and the empirical dietary index associated with lower inflammation (rEDIP) (0.53, 95% CI 0.39–0.72) for stomach cancer, and for the rEDIP (0.58, 95% CI 0.37–0.92) for small intestine cancer. Among accessory cancers, the Alternate Healthy Eating Index-2010, alternate Mediterranean diet, and diabetes risk reduction diet were associated with a 43%–51% lower risk of liver cancer. The reversed empirical dietary index for hyperinsulinemia, rEDIP, and the Alternate Healthy Eating Index-2010 were inversely associated with the risk of fatal DSC.DISCUSSION:Adherence to healthy diets was associated with a lower risk of incident and fatal DSC, although the magnitude of the association varied slightly among the patterns.