Background Psoriasis is a chronic disease that affects public health and budget payers. In Brazil, biologic therapy for psoriasis is mostly provided by means of lawsuit with no strategy for efficient allocation of resources. Objective This study aimed to identify which of the available biologic alternatives for psoriasis is the most efficient from the perspective of the Brazilian Public Health Service (SUS). Methods Direct costs and efficacy were expressed in Brazilian currency (real [R $]; US $1= R $1.97) and Psoriasis Area Severity Index 75 (PASI75), respectively. The Markov model process included 12 cycles of 3 months each, comprising 3 years of horizon. Adalimumab (80 mg at week 0 followed by a maintenance dose of 40 mg at week 1 and then every other week), etanercept (50 mg twice weekly for 12 weeks followed by a maintenance dose of 25 mg weekly), infliximab (5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks), and ustekinumab (45 mg at weeks 0 and 4 and then every 12 weeks) were assessed. One-way and horizon sensitivity analyses were performed. Moreover, probabilistic sensitivity analysis was applied to evaluate model robustness. The final result was interpreted as the cost for each patient who achieved and maintained PASI75 for at least 3 years. Results Adalimumab was the most cost-effective biologic therapy (R $120,981.45/PASI75) for moderate-to-severe psoriasis, followed by ustekinumab (R $126,336.67/PASI75), etanercept (R $225,074.71/PASI75), and infliximab (R $377,656.28/PASI75). One-way sensitivity analysis determined that the acquisition cost of biologics was the most sensitive parameter of the model. Horizon analysis suggests that the result was the same when the horizon was varied from 1 year to a lifetime. Probabilistic sensitivity analysis showed that adalimumab has 80% to 10% probability of being the most cost-effective biologic considering a willingness-to-pay value ranging from R $50,000 to R $500,000, whereas ustekinumab presented a probability of 20% to 90% for the same range. Conclusions From the pharmacoeconomics point of view, adalimumab 80 mg at week 0 followed by a maintenance dose of 40 mg at week 1 and then every other week should be the first-line therapy for patients with plaque psoriasis concomitant or not to psoriatic arthritis or nail psoriasis. This study does not have the potential to evaluate the impact of incorporating a specific biologic agent on the final budget. Its goal is to point out which of the technologies is the most efficient, that is, the one that adds more value to the financial resource invested.