Evidence on the use of direct oral anticoagulants (DOACs) in upper extremity deep vein thrombosis (UEDVT) remains limited. This study examines real-world outcomes of DOACs compared with standard anticoagulation therapy for UEDVT patients.Using the RIETE (Registro Informatizado de Enfermedad TromboEmbólica) database, we conducted an observational analysis of UEDVT patients treated with DOACs or standard therapy (low molecular weight heparin [LMWH] or vitamin K antagonists for noncancer patients, and LMWH for cancer patients). Patients with events during the first 5 days of treatment were excluded. The primary outcome was a composite of venous thromboembolism (VTE) recurrence and major bleeding during the first 3 months of therapy. Multivariable and multilevel analyses were conducted to adjust for confounding.Between January 2011 and November 2023, 3,496 UEDVT patients met the inclusion criteria. Of these, 679 (19.4%) received DOACs, whereas 2,817 (80.6%) received standard therapy. The composite outcome occurred in seven patients (1.0%) on DOACs (5 [0.7%] VTE recurrence, 2 [0.3%] major bleeding) compared with 78 patients (2.8%) on standard therapy (51 [1.8%] VTE recurrence, 29 [1.0%] major bleeding; p < 0.001). Multivariable analysis showed that DOAC use was associated with a lower risk of the composite outcome (adjusted subhazard ratio: 0.41; 95% confidence interval: 0.19-0.90). These findings remained consistent in multilevel models and sensitivity analyses stratified by cancer and catheter-related thrombosis.This real-world analysis suggests that DOACs may be associated with a lower risk of VTE recurrence and major bleeding compared with standard therapy in patients with UEDVT. These findings support DOACs as a viable treatment option.