Abstract: Background: Little is known about the impact of opioid safety initiatives (OSIs) on veterans with end-stage kidney disease on hemodialysis, a seriously ill population for whom balancing the benefits and harms of opioids can be challenging. Objective: To assess temporal trends and outcomes before and after the implementation of the Veterans Health Administration's (VA) OSI. Settings/Subjects: We conducted a cross-sectional study analyzing U.S. veterans who received VA-financed maintenance hemodialysis, either in the VA or under the VA Community Care program, from October 2009 to September 2019. Measurements: We assessed trends over time in the rates of outpatient opioid prescribing, moderate to severe pain, opioid overdoses, and use of nonpharmacological therapies. Data from VA, Medicare, and the United States Renal Data System were used. The unit of analysis was the patient-quarter. Results: We identified 44,557 veterans; 97.2% were male, 50.7% were White, and 61.6% were over age 65. The OSI was associated with a 10.28 percentage point (pp) reduction (95% confidence interval [CI]: -12.37, -8.19) in opioid prescribing and a 1.93 pp increase (95% CI: 0.30, 3.56) in the use of nonpharmacological therapies. The overdose rate decreased by 0.27 pp (95% CI: -0.54, -0.003), but the rate of reported moderate to severe pain increased by 3.21 pp (95% CI: 1.01, 5.40). These trends generally persisted among patients with different mortality risks. Conclusions: Our findings suggest that in the VA dialysis population, the VA OSI was associated with reductions in opioid use and modest decreases in opioid overdose but with limited uptake of nonpharmacological therapies and measurable increases in moderate to severe pain. These findings suggest the importance of an individualized patient-centered approach to opioid prescribing and research on nonpharmacologic alternatives in this population.