Objective: To assess the real-world risk of developing adverse medical conditions (AMCs) among patients with psoriasis treated with biologic therapies or conventional systemic/topical therapies (CST/topical). Methods: Adult patients with psoriasis were identified from the Truven MarketScan US claims database (2008 Q3–2015 Q3) and classified into cohorts based on treatment initiated on the index date (adalimumab [ADA], etanercept [ETN], ustekinumab [UST], infliximab [IFX], or CST/topical). Incident AMCs were identified while on treatment from diagnoses recorded in medical claims and included abnormal test results, infections, mental disorders, cardiovascular disease, malignancies (skin and non-skin), and respiratory disease. Cox proportional hazards models were used to compare AMC risk for (1) ADA, ETN, and UST (separately) vs CST/topical, and (2) ADA vs other biologic therapies (ETN, UST, and IFX combined). Regressions were adjusted for age, gender, region, insurance plan type, year, Charlson comorbidity index, and prior AMCs; and based on stepwise selection, comorbidities, specialist encounters, and frequently prescribed treatments. Results: A total of 42,981 patients were identified (ADA: 5,197; ETN: 3,311; UST: 1,370; IFX: 187; CST/topical: 32,916). Across cohorts, median age was 46–50 years, 46.2%–53.1% were female, and median follow-up duration was 3.3–7.9 months. For all cohorts, infection was the most frequent AMC (28.7%–41.8%). Compared with CST/topical, ADA, ETN, and UST were associated with a lower risk of infections (adjusted hazard ratio [aHR]: 0.93, 0.92, and 0.86, respectively, all P<0.05). ADA was associated with a lower risk of malignancies (aHR: 0.71, P<0.05), and ETN was associated with a lower risk of respiratory disease (aHR: 0.80, P<0.05). Compared with biologic therapies, ADA was not associated with higher risk of AMCs. Conclusions: Compared to CST/topical, biologic therapies were associated with similar or lower risk of AMCs. Comparison between ADA and other biologic therapies suggests a similar safety profile with respect to the studied AMCs.