OBJECTIVES This analysis examined the impact of ustekinumab on overall health-related quality of life (HRQoL). METHODS A total of 766 patients were enrolled in the PHOENIX 1 study. Patients were randomized to one of three treatment groups in a 1:1:1 ratio: a) placebo; b) ustekinumab 45 mg; and c) ustekinumab 90 mg. In the ustekinumab groups, patients received treatment at baseline, week 4, and every 12 weeks thereafter. Patients randomized to placebo at baseline crossed-over to receive 45 mg or 90 mg ustekinumab at week 12, 16, then every 12 weeks. Overall HRQoL was assessed using the MOS Short-Form 36 (SF-36). Analysis of variance was used to compare improvement in the physical and mental component summary (PCS, MCS) scores between treatment groups. RESULTS Baseline SF-36 scores were similar across treatment groups, with a mean PCS score of 47.9 and a mean MCS score of 49.8. Compared with patients in the placebo group, patients in each ustekinumab dose group (45 and 90 mg) had significantly greater improvements from baseline in both PCS (2.0 and 3.2, vs. –0.5, p values <0.001) and MCS (2.1 and 2.5 vs. –1.3, p values <0.001) scores at week 12. The improvements observed in the ustekinumab groups at week 12 were maintained through week 40. All 8 domains of the SF-36 showed significant improvements (p<0.02) in the combined ustekinumab group versus placebo at week 12. At week 40, patients in the placebo group who had crossed-over to ustekinumab (45 mg or 90 mg) at week 12 achieved improvements in PCS (2.7) and MCS (2.0) scores that were similar in magnitude to those observed in patients initially randomized to ustekinumab. CONCLUSIONS Ustekinumab significantly improved overall quality of life related to both physical and mental health in patients with moderate-to-severe psoriasis.