Abstract Background In contrast to vitamin K antagonists (VKA), direct oral anticoagulants (DOAC's) are not strictly monitored and dose titrated by anticoagulation clinics in the Netherlands. This may affect drug persistence of atrial fibrillation (AF) patients, whom often require lifelong treatment. Objectives To assess persistence of DOACs and of VKAs in patients with AF. Methods Dispensing data from the Dutch Foundation of Pharmaceutical Statistics were used to monitor persistence of AF patients to DOAC from 1 January 2012‐1 April 2016. In addition, we estimated the persistence of AF patients to VKA between 1 January 2004 and 1 January 2012 in data from the Anticoagulation Clinic Leiden. Non‐persistence was defined as the cumulative incidence of patients who completely stopped DOAC, switched to another oral anticoagulant or stopped their VKA. Results DOAC users (n = 77 333) were younger than VKA users (n = 10 079; 70 vs 73 years). Non‐Persistence to DOAC (ie stopping with any oral anticoagulant) was 34% at 1 and 64% at 4 years, compared to 22% at one and 36% at 4 years for VKA. Approximately a Twenty‐five percent of those who had stopped their initial DOAC switched to another anticoagulant (VKA or another DOAC). Multivariable analyses revealed that young age, female sex, no concomitant drug use and non‐adherence were predictors for non‐persistence of DOAC. Conclusions Persistence to DOAC was low and in line with other observational studies, and higher for VKA. Our results show a clear correlation between age <60 years and worse persistence, as well as with female and non‐adherence to DOAC.