The prophylactic and therapeutic anti-ischemic efficacy of isosorbide dinitrate (ISDN) oral spray was assessed in 10 patients with coronary artery disease and stable angina pectoris. The patients entered a randomized crossover study of ISDN spray and placebo, involving bicycle exercise testing. Each patient underwent 2 exercise tests at least 4 hours apart. Immediately before initiation of exercise they received either ISDN spray or placebo and crossed over during the other test. ISDN spray delayed the onset of anginal pain by about 40%, from a mean of 5.1 ± 1.4 minutes with placebo to 7.2 ± 1.3 minutes with the active drug (p < 0.001). Time of onset of ST-segment depression was also significantly prolonged, from 7.1 ± 1.5 minutes with placebo to 10.2 ± 1.2 minutes with ISDN (p < 0.001). The patients achieved a higher double product at onset of pain with ISDN than with placebo. The drug also reduced the time of disappearance of pain after discontinuation of exercise from 3.2 ± 0.7 to 2.1 ± 0.8 minutes (p < 0.001), and the time of disappearance of electrocardiographic changes from 4.2 ± 0.6 to 2.5 ± 0.8 minutes (p < 0.005). These findings indicate that oral ISDN spray is an effective prophylactic for exercise-induced angina. Its rapid onset of action makes it especially suitable for usage immediately before exercise.