INTRODUCTION: The long-term benefit-risk profiles of licensed and investigational treatments for moderate-to-severe plaque psoriasis have not been fully characterized. METHODS: Randomized controlled trials (RCTs) of licensed and investigational treatments for moderate-to-severe plaque psoriasis were identified through a systematic literature review through 2 May 2021. Bayesian network meta-analyses (NMAs) were conducted to compare the efficacy (Psoriasis Area and Severity Index [PASI] 75/90/100 [at least a 75/90/100% reduction in PASI score from baseline] response) and safety outcomes (any adverse event [AE], any serious AE [SAE], and AEs leading to treatment discontinuation) of each treatment evaluated between weeks 48 and 56 after baseline. Surfaces under the cumulative ranking curves (SUCRAs) were calculated to evaluate the relative ranking of treatments. The benefit-risk profiles of treatments were assessed by bidimensional plots of the NMA-estimated efficacy and safety outcomes. RESULTS: In the efficacy NMA (N = 14 RCTs), the relative rankings for PASI 75/90/100 responses by weeks 48-56 were the highest for risankizumab (SUCRA: 98.5%) and bimekizumab (83.8% for dosing every 4 weeks [Q4W], 72.7% for dosing Q4W then every 8 weeks). The PASI response rates did not differ significantly between risankizumab and the two bimekizumab regimens. Additionally, risankizumab was associated with significantly higher PASI response rates than brodalumab, guselkumab, ixekizumab, secukinumab, ustekinumab, adalimumab, and etanercept. In the safety NMAs (N = 8 RCTs), risankizumab had the highest relative rankings for all three outcomes (SUCRA: 92.1%, 82.0%, and 91.0% for any AE, any SAE, and AEs leading to treatment discontinuation, respectively). Risankizumab had a significantly lower rate of any AE than bimekizumab, ustekinumab, and secukinumab. CONCLUSIONS: Risankizumab was associated with the most favorable long-term benefit-risk profile for the treatment of moderate-to-severe plaque psoriasis. Although ixekizumab and bimekizumab had favorable efficacy profiles, both treatments had lower rankings for safety outcomes.