Importance Achieving good disease control in psoriatic arthritis (PsA) remains a major challenge. Combining multiple systemic immunomodulatory therapies has been shown to be beneficial in other immune-mediated diseases with reasonable safety profiles, but data on the current use and safety of combination targeted therapy among individuals with PsA are limited. Objective To evaluate the use and safety of combination targeted therapies among adults with PsA. Design, Setting, and Participants Data from the IBM MarketScan Commercial Claims Database from January 2015 to December 2024 were used to describe use patterns and perform safety analyses. Data were analyzed from April 2024 to June 2025. A validated claims algorithm was used to identify adults with PsA, who were separated into a standard therapy control cohort that was matched 2:1 with the combination targeted therapy cohort. Main Outcomes and Measures Descriptive analysis of the use of combination targeted therapies. The safety analysis included a comparison of frequencies of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) codes for serious or opportunistic infections requiring an inpatient level of care. Relative risks (RRs) were calculated before and after propensity score matching. Results Among 82 399 individuals identified with PsA, 542 individuals (median [IQR] age, 52.5 [44.0-59.0] years; 341 female individuals [62.9%]) were receiving combination targeted therapy for 3 consecutive months and 200 (median [IQR] age, 55.0 [45.0-61.0] years; 114 female individuals [57.0%]) were receiving combination therapy for 6 consecutive months. The 2 most common combinations used were a tumor necrosis factor inhibitor with apremilast (34%-37%) and an interleukin 17 inhibitor with apremilast (27%-29%). The serious infection incidence rate among patients receiving combination targeted therapy ranged from 7.38 to 15.00 events per 1000 patients; the opportunistic infection incidence rate ranged from 0 to 1.85 events per 1000 patients. Patients receiving combination targeted therapy did not have a significantly increased risk of serious infection (propensity score–matched 3-month and 6-month RRs, 0.53 [95% CI, 0.17-1.63] and 1.50 [95% CI, 0.34-6.65], respectively) or opportunistic infection (adjusted 3-month and 6-month RRs, 1.00 [95% CI, 0.09-11.02] and not applicable, respectively) across all analyses. Conclusions and Relevance The results of this cohort study suggest that among commercially insured adults with PsA, around 1% of individuals were receiving combination targeted therapy. The most common combinations used different biologics with apremilast. This study found no significant difference between the incidence of serious bacterial and opportunistic infections requiring hospitalization compared with standard therapy, suggesting that combination targeted therapy may not be associated with significantly increased infection risk, but further larger studies are needed.