OBJECTIVES:  To evaluate the comparative effectiveness of targeted immunomodulators for adults with moderate-to-severe plaque psoriasis. METHODS:  We performed a systematic literature review of randomized controlled trials of targeted immunomodulators – TNF-a inhibitors (adalimumab, etanercept, infliximab), ustekinumab, IL-17A inhibitors (secukinumab, ixekizumab, brodalumab), and apremilast (the only oral agent) – that evaluated the comparative clinical benefits or harms relative to placebo or each another. We searched and included studies from MEDLINE, EMBASE, and Cochrane-indexed articles, as well as “grey literature” sources such as conference abstracts. The primary outcome in nearly all trials was a 75% improvement on the Psoriasis Area and Severity Index (PASI 75) during induction (10-16 weeks). To evaluate direct and indirect comparisons, we conducted a network meta-analysis (NMA) using a multinomial model within a Bayesian framework and adjusted for placebo response. RESULTS:  We identified 36 RCTs, which included 8 direct comparisons. Across trials, the average participant was 43-46 years old and had psoriasis for 17-20 years; 22-30% had psoriatic arthritis and the baseline PASI score was 19-30. In placebo-controlled trials, patients on targeted immunomodulators had markedly higher rates of PASI 75 response (29% to 90%) than patients who received placebo (2% to 19%). In head-to-head trials, PASI 75 response rates were higher for ustekinumab (68-74%), secukinumab (77%), and ixekizumab (87-90%) versus etanercept (42-57%) and were higher for secukinumab (91%), brodalumab (85-86%), and ixekizumab (91%) versus ustekinumab (69-79%). In the NMA, the targeted immunomodulators ordered by an increasing relative risk of achieving PASI 75 during induction relative to placebo were apremilast (6.2), etanercept (9.6), adalimumab (13.0), ustekinumab (14.0), secukinumab (15.4), infliximab (16.2), brodalumab (17.3), and ixekizumab (17.9). CONCLUSIONS:  In general, IL-17A inhibitors are more effective than ustekinumab, which are, in turn, generally more effective than etanercept, adalimumab, and apremilast.