The underlying mechanisms of myocardial ischemia in microvascular angina may include endothelial dysfunction, abnormal smooth muscle tone, and abnormal autonomic control of coronary microvasculatures. This randomized, double-blind, placebo-controlled, crossover study was conducted to evaluate the effect of nicorandil (a nitrate-potassium channel opener) therapy on exercise-induced myocardial ischemia and cardiac autonomic activity in 13 patients with microvascular angina. After a 2-week placebo run-in period, patients were randomly assigned to the first 2-week treatment with nicorandil 5 mg tid or placebo, then crossed over to the second 2-week treatment after a 2-week washout period. Treadmill exercise tests and 24-hour ambulatory electrocardiogram monitoring were performed at the end of each treatment phase. The results showed that both time to 1-mm ST depression and total exercise duration were significantly prolonged with nicorandil treatment compared with placebo (p = 0.026 and 0.036, respectively). Maximum exercise ST depression also tended to be less with nicorandil treatment than with placebo (p = 0.083). Compared with 10 healthy control subjects, study patients had significantly reduced heart rate variability in both low- and high-frequency bands while receiving placebo. Nicorandil treatment did not change the altered heart rate variability in either time domain or spectral analysis. Systemic hemodynamics were also unchanged with nicorandil treatment. Thus, 2-week oral nicorandil therapy moderately improved exercise-induced myocardial ischemia without modifying the already altered cardiac autonomic activity, suggesting that nicorandil might have a direct vasodilatory effect on coronary microvasculatures in patients with microvascular angina.