It is not clear to what extent changes in blood pressure (BP) during hemodialysis affect or predict survival. Studying comparative outcomes of BP changes during hemodialysis can have major clinical implications including the impact on management strategies in hemodialysis patients. Here we undertook a retrospective cohort study of 113,255 hemodialysis patients over a 5 year period to evaluate an association between change in BP during hemodialysis and mortality. The change in BP was defined as post- minus pre-hemodialysis BP and mean of BP change values during the hemodialysis session was used as a mortality predictor. The patients averaged 61 years old and consisted of 45% women, 32% African-Americans and 58% diabetics. Over a median follow-up of 2.2 years, a total of 53,461 (47.2%) all-cause and 21,548 (25.7%) cardiovascular deaths occurred. In fully adjusted Cox regression model with restricted cubic splines, there was a U-shaped association between change systolic BP and all-cause mortality. Post-dialytic drops in systolic BP between −30 to 0 mmHg were associated with greater survival, but large decreases of systolic BP (more than −30 mmHg) and any increase in systolic BP (over 0 mmHg) were related to increased mortality. Peak survival was found at a change in systolic BP of −14 mmHg. The U-shaped association was also found for cardiovascular mortality. Thus, modest declines in BP after hemodialysis are associated with the greatest survival, whereas any rise or large decline in BP is associated with worsened survival.