Thirty six patients with documented coronary artery disease and exercise-induced silent ischemia were evaluated in a double-blind randomised placebo-controlled crossover study. The effect of once daily 60 mg sustained-release isosorbide-5-mononitrate (IS-5-MN) was tested on exercise-induced and ambulatory silent ischemia. After a wash-out period in which no cardioactive drugs were administered, each patient received IS-5-MN for the first week, followed by placebo for the second week, or vice versa. A symptom-limited bicycle exercise test and Holter monitoring over a 24-hour period were performed after wash-out and at the end of each one-week treatment period. In comparison with wash-out IS-5-MN significantly (p < 0.05) prolonged time on onset of 1 mm ST-segment depression during exercise testing. On the other hand, the number and circadian variation of ischemic episodes during Holter monitoring were not influenced by IS-5-MN. Thus, 60 mg IS-5-MN once daily significantly improved silent ischemia during exercise testing but not during Holter monitoring. This discrepancy may be due to different pathogenetic mechanisms of ischemia during ergometry as opposed to the everyday situation; nitrates may also provoke silent ischemia by increasing the heart rate. Furthermore, the choice of only one antiischemic drug at a fixed dosage may not be aggressive enough in suppressing ischemia completely.