OBJECTIVES: Limited information is available on the cost effectiveness of newer biologic agents for treatment of psoriasis.  The objective of this study is, from a United States societal perspective, to compare the cost-effectiveness of etanercept and ustekinumab therapy in patients with moderate-to-severe psoriasis based on head-to-head clinical trial information.   METHODS: A Markov model was constructed to simulate the incremental cost per quality-adjusted life year gained.  Costs were estimated from the societal perspective in the United States over a time horizon of five years.  All cost and effectiveness estimates were obtained from the relevant literature.  An annual discount rate of 3% was applied to costs and quality-adjusted life years.  All costs were adjusted to 2011 US dollars.  One-way and threshold sensitivity analyses assessed the robustness of model results.   RESULTS: In the base case, over a 5-year time horizon, ustekinumab 45 mg was dominant versus etanercept 50 mg.  The base case incremental cost-effectiveness ratio (ICER) comparing ustekinumab 90 mg with etanercept 50 mg averaged $267,761 per QALY gained.  The ICER comparing ustekinumab 90 mg with ustekinumab 45 mg averaged $915,179 per QALY gained.  ICERs were quite sensitive to unit prices for ustekinumab and etanercept.  CONCLUSIONS: Given the limitations of the available data, ustekinumab 45 mg was dominant over etanercept 50 mg for a five-year time horizon, whereas ustekinumab 90 mg was more costly and marginally more effective than etanercerpt 50 mg.  Ustekinumab 90 mg would not be considered cost effective using a US willingness-to-pay threshold of $120,000-150,000 per QALY.