INTRODUCTION: Moderate-to-severe plaque psoriasis is a chronic disease impacting quality of life (QoL). This network meta-analysis (NMA) compared efficacy and safety of all biologics approved for the treatment of moderate-to-severe plaque psoriasis to better inform providers on mid-term outcomes, with a focus on the interleukin-23 p19 inhibitor tildrakizumab. METHODS: MEDLINE®, Embase, and CENTRAL were searched for randomized clinical trials (RCT) from inception through January 2024. RCTs comparing biologics against placebo or each other reporting Psoriasis Area and Severity Index (PASI), Physician Global Assessment (PGA) 0/1, or Dermatology Life Quality Index (DLQI) 0/1 responses and safety outcomes (adverse events [AEs] or serious AEs [SAEs]) were sought. Bayesian NMAs were performed at week 28 as the primary time point of interest. Analyses were also performed at weeks 12 and 16. Findings were expressed as risk ratios (RR; efficacy outcomes), risk differences (RD; safety outcomes), and numbers needed to treat (NNT) with 95% credible intervals. RESULTS: Of 7418 publications screened, 187 describing 124 RCTs of 12 biologics were included in the systematic literature review, and 103 RCTs were included for NMA. All treatments demonstrated improved efficacy and QoL vs. placebo at week 28. Tildrakizumab efficacy at week 28 was comparable to risankizumab and guselkumab, respectively, for PASI 75 (RR 8.74 vs. 8.92 and 8.91), PASI 90 (RR 14.09 vs. 14.81 and 14.77), and PGA 0/1 (RR 9.34 vs. 10.29 and 10.23). No biologics exhibited an increased risk of SAEs vs. placebo; tildrakizumab exhibited no increased risk vs. placebo for AEs. CONCLUSIONS: The investigated biologics demonstrated improved efficacy and QoL relative to placebo at week 28, with no increased risk of SAEs vs. placebo through week 16. At week 28, efficacy of tildrakizumab, risankizumab, and guselkumab was comparable. Limitations include lack of placebo comparators after week 12 or 16, which could affect results.