: Oral anticoagulation (OAC) is pivotal in the clinical management of atrial fibrillation (AF) patients. Vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs) prevent thromboembolic events, but information about the quality of life (QoL) and patient satisfaction in relation with the anticoagulant treatment is limited. : REGUEIFA is a prospective, observational, and multicentre study that included patients with AF treated by cardiologists. We included patients treated with VKAs or DOACs. The EuroQol-5D (EQ-5D) questionnaire evaluated QoL, and the Anti-Clot Treatment Scale (ACTS) questionnaire investigated patient satisfaction with OAC. : A total of 904 patients were included (532 on VKA and 372 on DOACs). A total of 846 patients completed the EQ-5D questionnaire, with results significantly worse in patients on VKAs than on DOACs: more mobility limitations (37.6% vs. 24.2%, < 0.001), more restriction in usual activities (24.7% vs. 18.3%, = 0.026), more pain/discomfort (31.8% vs. 24.2%, = 0.015), a lower visual analogue scale (VAS) score (66.4 ± 16.21 vs. 70.8 ± 15.6), and a lower EQ-D5 index (0.79 ± 0.21 vs. 0.85 ± 0.2, < 0.001). After adjusting for baseline characteristics, VKA treatment was not an independent factor towards worse EQ-5D results. Also, 738 patients completed the ACTS questionnaire, and burden and profit scores were lower in patients on VKAs than for DOACs (52.1 ± 8.4 vs. 55.5 ± 6.8, < 0.001 and 11.1 ± 2.4 vs. 11.8 ± 2.6, < 0.001, respectively). The negative impact score was higher for VKAs than for DOACs (1.8 ± 1.02 vs. 1.6 ± 0.99, < 0.001), with a general positive impact score lower for VKAs than for DOACs (3.6 ± 0.96 vs. 3.8 ± 1.02, < 0.001). : Patients on VKA have more comorbidity and worse EQ-5D and VAS scores than those on DOACs. VKA has a greater burden and higher negative impact on the patient's life than DOACs.