ObjectiveThe objective of this study was to compare the clinical effectiveness of biologic disease‐modifying antirheumatic drugs (bDMARDs) or Janus kinase inhibitors (JAKi) among seropositive versus seronegative patients with rheumatoid arthritis (RA) in a real‐world setting.MethodsWe used Optum's deidentified Clinformatics Data Mart Database (January 1, 2004, to March 31, 2021) linked with outpatient laboratory test results. The study population was adult patients with RA who initiated a bDMARD or JAKi. The index date was the dispensing of the first‐ever study drug. At least 1‐year continuous enrollment before and after the index date was required. Disenrollment due to death after the index date was allowed. Serostatus was defined using laboratory test results or the International Classification of Diseases, 10th Revision code M05x or M06.0x any time prior to the index date. Treatment effectiveness was measured based on a claims‐based composite endpoint at 1‐year post index, including nonoccurrence of any of the following: addition of conventional synthetic DMARDs, addition of or switching to new bDMARDs/JAKi, initiation of glucocorticoids, increased glucocorticoid dose, or death. Log‐binomial regression models were constructed to estimate the risk ratio (RR) with 95% confidence interval (CI) comparing seropositive patients with seronegative patients, adjusting for more than 60 baseline covariates.ResultsWe identified a total of 7813 seropositive patients and 4202 seronegative patients. The mean (±SD) age was 56.7 (±14.0) years; 77.9% were female. The risk of 1‐year treatment effectiveness was 70.2% among seropositive patients and 69.8% among seronegative patients. The adjusted RR (95% CI) was 1.00 (0.98‐1.02).ConclusionIn this real‐world cohort study, seropositive and seronegative patients with RA had similar 1‐year treatment effectiveness after initiating a bDMARD/JAKi.