OBJECTIVES:  To determine the likelihood of cost-effectiveness, assessed by cost per quality-adjusted life year (QALY), for several targeted therapies approved to treat moderate-to-severe plaque psoriasis in the United States. Currently marketed drugs included were apremilast, adalimumab, etanercept, infliximab, ustekinumab, secukinumab, and ixekizumab; the newly-approved drug brodalumab was also included. METHODS:  We constructed a Markov model to simulate the flow of patients from first-line therapy to either second-line therapy or no treatment and, for patients receiving second-line treatment, from second-line therapy to no treatment. Patients were assumed to change treatment if they failed to achieve a 75% improvement in Psoriasis Area Severity Index (PASI-75) over baseline or if their response fell below PASI-75. The wholesale acquisition cost for each drug was discounted by a class-specific, empirically-derived rebate percentage. Brodalumab’s price was set to equal the average of secukinumab and ixekizumab, the other two IL-17 agents. Health-related utility on first-line treatment was derived from improvement in PASI score from baseline; second-line treatment used a weighted average of utility on targeted therapy, with a 5% decrement to represent loss of efficacy in patients with prior targeted therapy. We conducted a probabilistic sensitivity and net monetary benefit analysis to estimate likelihood of cost-effectiveness. RESULTS:  Over a ten year time horizon, at a willingness-to-pay of $100,000/QALY, secukinumab, ixekizumab, and brodalumab – all IL-17 agents – had a combined probability of 51% of being most cost-effective, while apremilast and infliximab had 11% and 7% probability, respectively. The class-wide probability of cost-effectiveness for IL-17 drugs rose to 94% when willingness-to-pay is $150,000/QALY. CONCLUSIONS: At and above the $100,000/QALY threshold often cited for the United States, the three IL-17 agents in this study are likely to be the most cost-effective first-line agents.