Background: Hypertension is present in nearly 80% of dialysis patients yet adequately controlled in less than half. We designed a stepped antihypertensive regimen using long-acting antihypertensives (trandolapril, atenolol and amlodipine) administered thrice a week (TIW) after each hemodialysis, and compared blood pressure (BP) control, medication cost and pill burden to each patient’s prior daily antihypertensive prescriptions. Methods: Patients were continued on their daily medications, pre-dialysis sitting BP was measured and a 44-hour interdialytic ambulatory BP monitoring (ABPM) was obtained. Then, their medications were stopped and replaced with trandolapril (2 mg TIW). Atenolol and/or amlodipine were also given TIW if the patients had any member of these classes of drugs as part of their daily regimen. Medications were titrated every 2 weeks to achieve a pre-dialysis mean arterial pressure (MAP) of <107 mm Hg. After 2 consecutive weeks with a pre-dialysis MAP of <107 mm Hg, a second 44-hour ABPM was obtained. Results: Ten patients completed the study. A persistent MAP of <107 was maintained in all 10 patients after conversion to TIW dosing. The systolic BP decreased from 122.2 ± 7.1 to 116.4 ± 11.6, and the diastolic BP decreased from 75.3 ± 10.4 to 70.4 ± 11.4 mm Hg. Pill burden and cost of medications were also significantly less. Conclusions: This pilot study found that ACE inhibitor-based, directly observed TIW therapy to be effective in hemodialysis patients with mild to moderate hypertension. Larger trials of directly observed therapy for hypertension in dialysis patients are warranted.