OBJECTIVE To compare the efficacy of ustekinumab with that of other biological agents using the Psoriasis Area and Severity Index (PASI) among adult patients with moderate to severe plaque psoriasis. DATA SOURCES We conducted a systematic search of the period January 31, 1992, to February 1, 2012, using MEDLINE (PubMed), Embase, the Cochrane Library, and clinicaltrials.gov. STUDY SELECTION We included randomized controlled trials of biological agents compared with placebo or other biological agents using the PASI in patients who had moderate to severe plaque psoriasis. DATA EXTRACTION Study data were extracted independently by 2 of us, with disagreement resolved by consensus. Data extracted included the size of the trial, follow-up period, age range of patients, disease duration, body surface area involvement, baseline PASI, PASI response, and previous treatment with biological agents. DATA SYNTHESIS A Bayesian network meta-analysis was performed by fitting 3 regression models: a fixed-effects model, a random-effects model, and a random-effects model with meta-regression coefficients. The random-effects model achieved the best fit for these data. In pairwise comparisons, ustekinumab use was associated with statistically significantly higher odds for achieving a 75% reduction in the PASI compared with adalimumab use (odds ratio [OR], 1.84; 95% credible interval [CrI], 1.01-3.54), alefacept use (OR, 10.38; CrI, 3.44-27.62), and etanercept use (OR, 2.07; 95% CrI, 1.42-3.06) but was associated with lower odds compared with infliximab use (OR, 0.36; 95% CrI, 0.14-0.82) . In the therapeutic class comparison, the interleukin-12/23 inhibitor had the highest odds for achieving a 75% reduction in the PASI compared with placebo (OR, 69.48; 95% CrI, 36.89-136.46), followed by tumor necrosis factor inhibitors (OR, 42.22; 95% CrI, 27.94-69.34) and the T-cell inhibitor (OR, 5.63; 95% CrI, 1.35-24.24). CONCLUSION For the treatment of moderate to severe plaque psoriasis, ustekinumab may be more efficacious than adalimumab, etanercept, and alefacept but not infliximab.