The effects of systemic therapy on mortality risk among patients with psoriasis are not fully understood.To evaluate the impact of systemic treatment on mortality risk in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR).Nested case-control analyses were performed to estimate mortality risk. Cases were defined as patients who died while participating in PSOLAR. Cases were matched (1:4) with controls by age, race, gender, and geographic region. Evaluated treatments included methotrexate, ustekinumab, and tumor necrosis factor-α inhibitors. Exposure was defined as ≥1 dose of treatment within 3 months prior to death and was stratified by duration of therapy.Among 12,090 patients, 341 deaths occurred, matched to 1364 controls. Biologic treatment within the preceding 3 months was protective against mortality versus no exposure; odds ratio (OR) for exposure <1 year, 0.08 (95% confidence interval: 0.03, 0.23); OR for exposure ≥1 year, 0.09 (0.06, 0.13). Methotrexate was protective against mortality only with exposure for ≥1 year (OR, 0.08 [0.02, 0.28]).Observational studies are subject to unmeasured confounding.Biologic therapy was associated with reduced mortality risk in patients with moderate-to-severe psoriasis, regardless of treatment duration; methotrexate reduced risk only with exposure for ≥1 year.