The aim of our study was to investigate the effect of transdermal nitroglycerin (NTG) on effort-induced silent myocardial ischemia in asymptomatic patients treated with beta-blockers or calcium antagonists. The acute effect was compared to two different schedules, continuous (24h/day) or intermittent (16 h/day), of long-term administration. Ten asymptomatic patients with coronary artery disease and a treadmill test positive for ischemia without angina were enrolled. Both acute (2 days) and long-term (24 days) evaluations were conducted in a randomized, double-blind, crossover fashion. The ergometric parameters were collected on the 1st and the 2nd day of the acute phase (placebo and transdermal NTG, respectively) and at the end of each 12-day period of long-term administration (continuous and intermittent, respectively). Transdermal NTG administration acutely increased (p < 0.05) both time to 1-mm ST segment depression (451 ± 43.2 vs. 374 ± 24.1 s) and total exercise time (561.3 ± 43.2vs.419.5 ± 24.5 s). The acute efficacy was maintained over long-term treatment, regardless of the modality of administration. During continuous and intermittent patch application, time to 1-mm ST segment depression was 437.9 ± 30.4 and 422 ± 33.4 s (p = NS vs. acute) and total exercise time was 498.8 ± 30.4 and 495.1 ± 33 s (p = NS vs. acute), respectively. Transdermal NTG increases, both acutely and chronically, exercise tolerance in asymptomatic patients with effort-induced silent myocardial ischemia. With the NTG dose we used, tolerance does not seem to be a problem over long-term administration.