NO donor drugs (eg, isosorbide mononitrate; ISMN) and phosphodiesterase 5 inhibitors (eg, sildenafil) have antihypertensive properties, and the combination can markedly reduce blood pressure (BP). The objective of this "proof-of-concept" study was to investigate the effect on BP of a combination of single oral doses of sildenafil (50 mg) and ISMN (10 mg) in patients with treatment-resistant hypertension. Six subjects with treatment-resistant hypertension were included, and their usual antihypertensive medication was continued during the study. Sildenafil alone, ISMN alone, and the combination all reduced brachial and central aortic BPs compared with placebo. The combination of sildenafil and ISMN produced the largest fall in BP (maximum brachial BP reduction of 26/18 mm Hg compared with placebo), without producing significant adverse effects. ISMN, alone and in combination with sildenafil, also reduced arterial wave reflection and central BP. In summary, in patients with treatment-resistant hypertension maintained on their usual antihypertensive treatment, sildenafil given alone and ISMN given alone both acutely reduced BP. There was additional BP reduction when these drugs were given in combination. In this therapeutically challenging group of patients, the combination of an NO donor drug and a phosphodiesterase 5 inhibitor may represent an effective treatment. Longer studies in larger numbers of patients are now justified.