The Janus kinase inhibitor upadacitinib is a potential treatment for psoriatic arthritis. The efficacy and safety of upadacitinib as compared with adalimumab, a tumor necrosis factor α inhibitor, in patients who have an inadequate response to nonbiologic disease-modifying antirheumatic drugs are unclear. In a 24-week, phase 3 trial, we randomly assigned patients in a 1:1:1:1 ratio to receive oral upadacitinib at a dose of 15 mg or 30 mg once daily, placebo, or subcutaneous adalimumab (40 mg every other week). The primary end point was an American College of Rheumatology 20 (ACR20) response (≥20% decrease in the number of tender and swollen joints and ≥20% improvement in at least three of five other domains) at week 12 with upadacitinib as compared with placebo. Secondary end points included comparisons of upadacitinib with adalimumab. A total of 1704 patients received an active drug or placebo. The percentage of patients who had an ACR20 response at week 12 was 70.6% with 15-mg upadacitinib, 78.5% with 30-mg upadacitinib, 36.2% with placebo (P<0.001 for both upadacitinib doses vs. placebo), and 65.0% with adalimumab. The difference between groups for 15-mg upadacitinib as compared with adalimumab was 5.6 percentage points (95% confidence interval [CI], -0.6 to 11.8) and for 30-mg upadacitinib as compared with adalimumab was 13.5 percentage points (95% CI, 7.5 to 19.4). Both upadacitinib doses were noninferior to adalimumab for the ACR20 response at week 12; the 30-mg dose but not the 15-mg dose was superior to adalimumab. The incidence of adverse events through week 24 was 66.9% with 15-mg upadacitinib, 72.3% with 30-mg upadacitinib, 59.6% with placebo, and 64.8% with adalimumab. There were serious infections in 1.2%, 2.6%, 0.9%, and 0.7% of the patients, respectively. Hepatic disorders occurred in 9.1% of patients in the 15-mg upadacitinib group and 12.3% in the 30-mg upadacitinib group, but grade 3 increases in aminotransferase levels occurred in 2% of patients or fewer in all groups. The percentage of patients with psoriatic arthritis who had an ACR20 response at week 12 was significantly higher with 15-mg or 30-mg upadacitinib than with placebo. The 30-mg dose but not the 15-mg dose was superior to adalimumab. Adverse events were more frequent with upadacitinib than with placebo. (Funded by AbbVie; SELECT-PsA 1 ClinicalTrials.gov number, NCT03104400.). Copyright © 2021 Massachusetts Medical Society.