Resistant hypertension is a common health problem leading to suboptimal cardiovascular prevention. A large number of patients with resistant hypertension have poor medication adherence explaining their assumed resistance to therapy. We combined directly observed therapy (DOT) with therapeutic drug monitoring (TDM) in 3 patients at several time points to enable an extensive feedback on blood pressure (BP) and drug levels. BP was measured with an automatic oscillatory device at regular intervals of 5 minutes (directly before and after drug intake) and at 30-minute intervals (at night) during admission. Blood samples were obtained at different time points (t = in hours; t = 0, 2, 4, 6, 12, and 24 hours after drug intake). DOT was performed under supervision of the physician. In 2 of the 3 patients, automated BP decreased directly after DOT, −10/0 and −5/−5 mm Hg, respectively. Plasma drug levels for several drugs or active metabolites were 0 at t = 0, whereas plasma levels were positive at t = 24 hours after observed intake. We recommend a more frequent use of TDM combined with repeated BP measurements in clinical practice because this is a convenient, objective method of measurement and to ensure that actual drug levels reflect the BP at the time of measurement.