OBJECTIVES: The study aimed to (1) develop a cost model for colonoscopy preparation among patients referred for colonoscopy using split-dose reduced-volume oral sulfate solution (OSS) and generic polyethylene glycol with electrolytes solution (PEG-ELS), (2) examine cost-savings associated with OSS versus PEG-ELS, and (3) assess the robustness of the cost model. METHODS: Clinical efficacy of each agent was based on the results of a 541-patient clinical trial comparing OSS to PEG-ELS. Cleansing agent and colonoscopy procedure costs were calculated from OptumHealth Reporting & Insights claims data for 2010–Q12013. In the cost model, patients’ colonoscopies were tracked until the patient reached age 75. The difference per patient per year (PPPY) in total cleansing agent and colonoscopy procedure costs over the time horizon between the OSS and PEG-ELS cohort was calculated. One-way sensitivity analyses were also conducted to test the robustness of the cost model. RESULTS: The cost model showed that OSS patients had fewer colonoscopies over the time horizon (OSS: 0.158 vs. PEG-ELS: 0.170 PPPY). Total PPPY costs were $280.34 for the OSS cohort and $296.36 for the PEG-ELS cohort, resulting in a cost-saving of $16.01 to the payer for the OSS cohort. Varying the annual colonoscopy completion rate, surveillance intervals, time horizon, and proportion of high risk patients did not change the observation of cost-savings under OSS. Cost-savings switched from the OSS to the PEG-ELS cohort in three cases: (1) base-case cost of a completed colonoscopy decreased by 75%, (2) base-case cost of OSS increased to over $143 per usage, and (3) all non-completers were lost to follow up. CONCLUSIONS: From a payer’s perspective, the cost model showed that the use of OSS as the cleansing agent resulted in potential cost-savings compared with PEG-ELS. The cost model was robust and cost-savings under OSS remained under various sensitivity analyses.