ObjectivesCompare costs associated with all-cause healthcare resource use (HCRU), stroke/systemic thromboembolism (STE) and major bleedings (MB) between patients with non-valvular atrial fibrillation (NVAF) initiating apixaban or other oral anticoagulants (OACs).MethodsWe performed a retrospective cohort study using the French healthcare claims database, including NVAF patients between 2014/01/01 and 2016/12/31, followed until 2016/12/31. We used 4 sub-cohorts of OAC-naive patients, respectively initiating apixaban, dabigatran, rivaroxaban or VKAs. We matched patients initiating apixaban with patients initiating each other OACs using 1:n propensity score matching. All-cause HCRU and event-related costs by OAC treatment were estimated and compared between matched patients using generalised-linear models with gamma-distribution and two-part models.ResultsThere were 175,766 patients in the apixaban–VKA, 181,809 in the apixaban–rivaroxaban, and 42,490 in the apixaban–dabigatran matched cohorts. Patients initiating apixaban had significantly lower HCRU costs than patients initiating VKA (€1,105 vs. €1,578,p< 0.0001), dabigatran (€993 vs. €1,140,p< 0.0001) and rivaroxaban (€1,013 vs. €1,088p< 0.0001). They have had significantly lower costs related to stroke/STE and MB than patients initiating VKA (respectively, €183 vs. €449 and €147 vs. €413; p < 0.0001), rivaroxaban (respectively, €145 vs. €197 and €129 vs. €193;p< 0.0001), and lower costs related to stroke/STE than patients initiating dabigatran (€135 vs. €192,p< 0.02). Costs related to MB were not significantly different in patients initiating apixaban and those initiating dabigatran (€119 vs. €149,p= 0.07).ConclusionsHCRU and most event-related costs were lower in patients initiating apixaban compared to other OACs. Apixaban may be cost-saving compared to VKAs, and significantly cheaper than other DOACs, although cost differences are limited.Supplementary InformationThe online version contains supplementary material available at 10.1007/s10198-022-01513-2.