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Ustekinumab is highly efficacious for psoriasis; however, it has not been fully clarified whether previous failure in anti-tumor necrosis factor-α (TNF-α) therapy affects the treatment response with ustekinumab. Therefore, we evaluated the efficacy of ustekinumab in anti-TNF-α-naïve and anti-TNF-α-resistant cases and compared the clinical efficacies of adalimumab and ustekinumab in biologic naïve cases. Thirty-five patients with plaque psoriasis who showed resistance to conventional therapies were enrolled; 26 patients, who had never been treated with biologics, were allocated to ustekinumab or adalimumab; nine patients who failed to achieve psoriasis area and severity index (PASI) 50 at week 16 with one or two TNF-α antagonists were switched to ustekinumab. The end of the study was defined as 52 weeks after starting the first biologic for anti-TNF-α-naïve patients and after switching to ustekinumab for anti-TNF-α-resistant patients. The primary outcome measurement was the percentage of patients achieving PASI75 at week 16. In patients treated with ustekinumab, 87.5% of anti-TNF-α-naïve and 77.8% of anti-TNF-α-resistant cases achieved a PASI75 response at week 16, and no statistically significant difference was found between the treatment response rates (P = 0.60). When comparing the treatment efficacy of ustekinumab and adalimumab among anti-TNF-α-naïve patients, there was also no statistically significant difference in PASI75 achievement rates (87.5 vs. 83.3%, P = 0.79). Our study suggests that ustekinumab can be considered as a first-line biologic for psoriasis and a rescue therapy for anti-TNF-α-resistant cases.