Biologic agents are becoming the mainstay of therapy for patients with moderately to severely active Crohn’s Disease (CD). Better understanding of relative cost-effectiveness of drugs with new mechanisms of action is needed to help determine the optimal positioning of these therapies in the treatment algorithm and facilitate resource allocation decisions. OBJECTIVES: A cost-utility analysis was conducted to compare vedolizumab (VDZ) versus ustekinumab (UST) for treatment of patients with moderately to severely active CD from a third-party US payer perspective. METHODS: A model combining decision-tree and Markov structures was used to predict clinical and economic outcomes at the induction and maintenance phases of treatment. This analysis considered patients who were anti-TNF naïve/non-anti-TNF refractory at the time of VDZ/UST treatment initiation within 5-year, 10-year, and lifetime horizon. Efficacy data were derived from a Bayesian network meta-analysis of VDZ and UST phase 3 trials; other inputs were obtained from published literature. Only direct healthcare costs were considered. Clinical outcomes were expressed as quality-adjusted life-years (QALYs). Univariate and multivariate probabilistic sensitivity analyses (PSA) were conducted to assess model robustness to parameter uncertainty. RESULTS: : Patients treated with VDZ accrued more QALYs than patients treated with UST across all time horizons: 2.479 vs. 2.406 at 5 years, 4.308 vs. 4.220 at 10 years, 10.461 vs. 10.326 in lifetime analysis. The estimated cost difference was also in favor of VDZ: -$51,432 at 5 years, -$52,676 at 10 years, -$55,523 in lifetime analysis. Univariate sensitivity analyses suggested that results are mostly sensitive to treatment response; PSA showed that VDZ is dominant in 89.6% of the simulations. CONCLUSIONS: The model predicted that VDZ treatment results in a higher number of QALYs gained at lower cost compared with UST in CD patients who had not failed a prior anti-TNF agent. Additional comparative effectiveness studies to confirm these findings are warranted.