A retrospective cohort study compared the safety and efficacy of apixaban and rivaroxaban in the treatment of cancer-related venous thromboembolism (VTE) in patients from the Medicare (≥65 years, 2016–2020) and MarketScan (18–64 years, 2016–2022) databases. It included 6,329 patients on apixaban and 4,260 on rivaroxaban with active cancer diagnosed within 6 months before VTE who started treatment within 30 days. The main results at 6 months showed a similar risk of recurrent VTE (HR 0.66, 95% CI 0.40–1.11; p=0.11) and major bleeding (HR 0.95, 95% CI 0.73–1.23) with apixaban versus rivaroxaban. Apixaban had a lower risk of clinically relevant non-major bleeding (HR 0.84, 95% CI 0.74–0.96; p=0.009). These results persisted throughout the follow-up period. The analysis used inverse probability weighting to adjust for differences in demographics, comorbidities, and cancer treatment. The main limitation is the observational design with possible residual confounding.