Serious infection is a concern for patients with psoriasis on biologic therapies. We assessed the risk of serious infections of biologics used to treat psoriasis by comparison with a cohort on non-biologic systemic therapies in a propensity-score weighted Cox proportional hazards model using data from the British Association of Dermatologists Biologic Interventions Register (BADBIR). 1352, 3271 and 994 participants were included in the etanercept, adalimumab, ustekinumab cohorts respectively and 3421 participants in the non-biologic cohort. 283 patients had a serious infection; the incidence rates with 95% confidence interval (CI) /1000 person-years were: non-biologic 14.2 (11.5 to 17.4); etanercept 15.3 (11.6 to 20.1); adalimumab 13.9 (11.4 to 16.6); ustekinumab 15.1 (10.8 to 21.1). No significant increases in the risk of serious infection were observed for etanercept (hazard ratio (HR) 1.10 [95% CI 0.75 to 1.60]); adalimumab (HR 0.93 [0.69 to 1.26]) or ustekinumab (HR 0.92 [0.60 to 1.41]) compared against non-biologic systemic therapies or methotrexate only (etanercept HR 1.47 [0.95 to 2.28]; adalimumab HR 1.26 [0.86,1.84]; ustekinumab HR 1.22 [0.75,1.99]). The risk of serious infection should not be a key discriminator for patients and clinicians when choosing between non-biologic systemic therapies, etanercept, adalimumab and ustekinumab for the treatment of psoriasis.