Background Anti–tumor necrosis factor (TNF) therapy in psoriasis has been associated with an increased risk of serious infections compared with nonbiologic systemic therapies. Objective We sought to quantify the risk of: (1) serious infections (leading to hospitalization, sequelae, or death); and (2) “any infection,” bacterial cutaneous infections, and granulomatous infections among patients receiving anti–TNF therapy compared with nonbiologics (acitretin, methotrexate, cyclosporine). Methods We used prospective meta-analysis to combine data from the Psocare registry (Italy), Biobadaderm registry (Spain), and Clalit Health Services database (Israel), including 17,739 patients and 23,357.5 person-years of follow-up. Results For serious infections, age, gender, and Charlson morbidity index adjusted hazard ratio of exposure to anti–TNFs compared with nonbiologics was 0.98 (95% confidence interval 0.80-1.19), for bacterial cutaneous infections it was 1.00 (95% confidence interval 0.62-1.61), and for granulomatous infections it was 1.23 (95% confidence interval 0.82-1.84). Using methotrexate as comparator and comparing first year of exposure with later exposure did not modify the results. For any infectious episode, risks and relative risks were heterogeneous among registries, probably because of different definitions of outcome. Limitations There was lack of power to describe risk of single drugs. Conclusion In current clinical practice, treatment with anti–TNF drugs was not associated with a higher risk of serious infections than treatment with nonbiologic systemic therapy.