Abstract Background Direct-acting oral anticoagulants (DOACs) are widely prescribed for stroke prevention in patients with atrial fibrillation. An important advantage of DOACs is that routine monitoring of anticoagulation response is not necessary. Nevertheless, due to their mechanism of action, DOAC anticoagulation effect can be inferred based on observed plasma concentration. However, there is paucity of data relating to observed interpatient variation in DOAC plasma concentrations in the post-market clinical setting. Methods We determined rivaroxaban and apixaban plasma concentrations in atrial fibrillation patients during routine clinic visits. Results Among 243 patients (rivaroxaban, n=94; apixaban, n=149) enrolled in this study, 60- and 50-fold interpatient variation in plasma concentration was observed for rivaroxaban and apixaban respectively. Approximately 12% of rivaroxaban and 13% of apixaban patients exceeded the 95th percentile for predicted maximum plasma concentration observed in clinical trials. Conclusions In this routine care setting, rivaroxaban and apixaban plasma concentrations tended to be more variable than those observed in clinical trials. Identification of additional clinical and molecular determinants that more fully predict patients at risk for excessively high or low DOAC concentrations may enable a more precise DOAC dosing regimen for the individual patient.