Although the direct oral anticoagulants (DOACs) do not require routine laboratory monitoring, there may be special situations in which measurement of drug levels is desirable. There is a paucity of information on how measurement of DOAC levels is used in clinical practice. We conducted a retrospective cohort study of dabigatran, rivaroxaban, and apixaban levels measured at our institution. Of 9793 patients with an active prescription for dabigatran, rivaroxaban, or apixaban in the electronic medical record during the 2.5-year study period, 32 (0.33%) patients underwent a total of 37 DOAC measurements. Twenty patients were on rivaroxaban, 12 were on apixaban, and none was on dabigatran. The most common indications for measurement in inpatients were surgery, breakthrough thrombosis, and bleeding. In the ambulatory setting, patient characteristics suspected to lead to derangements in drug levels (eg, extremes of body weight, gastrointestinal malabsorptive disorders) served as a frequent indication. Among preoperative patients, DOAC levels influenced decisions about the timing of surgery. In most outpatients, levels were within expected ranges and affirmed current management. In a small number of patients with breakthrough thrombosis or bleeding, the identification of drug levels below or above expected concentrations led to a change in the anticoagulant regimen. In conclusion, DOAC measurement was infrequently requested. Indications differed between hospitalized patients and outpatients. Clinical response varied by drug level and indication.