Background and Aims: Nitrate therapy improves hemodynamics in patients with heart failure, but the chronic effects of oral nitrates on exercise performance and clinical status have not been well studied. Methods: Oral isosorbide-5-mononitrate (ISMN) (50 mg once daily) or placebo was administered to 136 patients (NYHA Class 2–3) treated for heart failure, all receiving captopril and most also furosemide. Endpoints were treadmill exercise time at 12 weeks by modified Naughton protocol (primary), with an additional 12-week follow-up period. Secondary endpoints included left ventricular dimensions, ejection fraction, cardiothoracic ratio, functional class, quality of life, hospitalizations and plasma norepinephrine and atrial natriuretic peptide in a four-center substudy. Results: Intention-to-treat analysis showed that mean change in treadmill exercise duration tended to be greater in patients receiving ISMN than placebo (treatment difference +42 s, 95% CI –5, +90 s at 12 weeks and +21 s, 95% CI –25, +74 s after 24 weeks) (NS). Treatment difference was greater in the prespecified subgroup with ejection fraction 31–40% (+55 s, 95% CI –11, +136 s at 12 weeks and +65 s, 95% CI +3, +147 s) (p = 0.035) at 24 weeks. No deleterious effects (i.e. hypotension) were observed with ISMN, although headache was reported in 19% of the active treatment group (p = 0.0001). Conclusions: ISMN added to captopril increased treadmill exercise time in patients with heart failure and a lesser reduction in baseline ejection fraction, although for the group as a whole, the increase in treadmill time was not significant.