Objective: Studies have shown that continuous and on-demand use of proton pump inhibitors (PPI) are more efficacious and cost-effective strategies than continuous histamine-2 receptor antagonist (H2RA) use for maintenance therapy of gastroesophageal reflux disease (GERD). Recent research has raised questions about potential safety concerns of hip fractures and acute myocardial infarction (AMI) associated with long-term PPI use. This study integrates treatment efficacy with emerging safety data to compare the cost-effectiveness from the payer perspective of continuous PPI use, on-demand PPI use, and continuous H2RA use for maintenance therapy for GERD. Methods: A Markov model was designed to simulate, over five years, the clinical and economic outcomes of GERD patients asymptomatic after initial acute treatment on maintenance therapy with PPIs or H2RA. The transition probabilities, costs, and utilities were derived from the peer-reviewed literature. Sensitivity analysis was conducted to examine the robustness of the model and to determine the thresholds at which safety issues may alter therapeutic decisions. Results: In the base-case efficacy model, intermittent PPI treatment was the least costly and least effective strategy, whereas the step-down PPI strategy was most costly and most effective, with an incremental cost-effectiveness ratio (ICER) of $24,636 per quality-adjusted life-year (QALY), relative to the intermittent PPI strategy. The maintenance H2RA strategy was dominated throughout the sensitivity analysis. The results were consistent when hip fracture events were introduced into the model, with the step-down PPI strategy ICER increasing to $29,113/QALY. Threshold analysis for AMI showed the hypothesized relative risk (RR) would need to be 11.9 before maintenance H2RA therapy would be considered a cost-effective alternative. Conclusion: Under all circumstances, strategies using PPIs are optimal for managing patients with GERD. Emerging concerns around hip fracture and AMI do not significantly affect the relative cost-effectiveness performance of alternative treatment strategies.