OBJECTIVES: To examine Number-Needed-to-Treat (NNT) and compare associated costs of care among treatments for moderate-to-severe psoriasis. METHODS: We conducted an Expert Panel systematic literature review of randomized, placebo-controlled trials for moderate-to-severe psoriasis. Study inclusion criteria were designed to minimize bias. Treatments included traditional oral systemics (acitretin and cyclosporine) and newer biologics (alefacept, efalizumab, etanercept, infliximab). For each treatment, we applied systematic literature review findings to calculate NNT (average number of patients required to achieve one additional treatment success compared to placebo). Treatment success was defined as 75% improvement on the Psoriasis Severity Area Index (PASI) or “clear/almost clear” status per physician global assessment (PGA). We used October, 2004 US Average Wholesale Drug Prices and 2004 Medicare Reimbursement Rates to estimate annualized total treatment costs (USD). Costs reflected the US managed health care payer perspective and comprised: medications + treatment administration (e.g., IV infusion) + monitoring (e.g., laboratory procedures) + risk-adjusted adverse events costs. RESULTS: NNT (95% CI) were: acitretin 50mg/day NNT=2 (1-6); alefacept 15mg/week NNT=5 (3-9); cyclosporine 3 mg/kg/day NNT=3 (2-6); efalizumab 1mg/kg/week NNT=5 (4-9); etanercept 50mg twice weekly NNT=2 (2-3); infliximab 5mg/kg weeks zero, two, six and bimonthly thereafter NNT=1 (1-1). Estimated annualized total treatment costs were: cyclosporine $6,951; acitretin $13,060; efalizumab $17,999; etanercept $21,158; infliximab $26,436; and alefacept $27,098. Using NNT results, we estimated the following annualized costs to achieve one treatment success: cyclosporine $20,853; acitretin $26,120; infliximab $26,436; etanercept $42,316; efalizumab $89,995; and alefacept $135,490. CONCLUSIONS: In an environment absent of head-to-head comparative trials, where burgeoning demand for newer and more costly treatments contends with limited healthcare resources, payors and providers seek alternative methods to compare safety, efficacy, and costs of treatment for moderate-to-severe psoriasis. Our NNT analysis suggests that although newer biologic treatments offer helpful treatment alternatives, traditional oral systemics may provide more cost-effective treatment options.