Background:There are concerns regarding the gastrointestinal (GI) safety of sodium polystyrene sulfonate (SPS), a medication commonly used in the management of hyperkalemia.Objective:To compare the risk of GI adverse events among users versus non-users of SPS in patients on maintenance hemodialysis.Design:International prospective cohort study.Setting:Seventeen countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018).Patients:50 147 adults on maintenance hemodialysis.Measurements:An adverse GI event defined by a GI hospitalization or GI fatality with SPS prescription compared with no SPS prescription.Methods:Overlap propensity score–weighted Cox models.Results:Sodium polystyrene sulfonate prescription was present in 13.4% of patients and ranged from 0.42% (Turkey) to 20.6% (Sweden) with 12.5% use in Canada. A total of 935 (1.9%) adverse GI events (140 [2.1%] with SPS, 795 [1.9%] with no SPS; absolute risk difference 0.2%) occurred. The weighted hazard ratio (HR) of a GI event was not elevated with SPS use compared with non-use (HR = 0.93, 95% confidence interval = 0.83-1.6). The results were consistent when examining fatal GI events and/or GI hospitalization separately.Limitations:Sodium polystyrene sulfonate dose and duration were unknown.Conclusions:Sodium polystyrene sulfonate use in patients on hemodialysis was not associated with a higher risk of an adverse GI event. Our findings suggest that SPS use is safe in an international cohort of maintenance hemodialysis patients.