In a randomized, double-blind, crossover study, 19 patients with angina were exercised 2 min after 0.4 mg sublingual nitroglycerin and after sublingual placebo and before and 1, 3, and 5 hours after oral isosorbide dinitrate (ISDN) and oral placebo. After initial testing, patients took the dose of ISDN they had had during the study (mean dose 29 mg) for a mean period of 5.6 months before retesting using the same protocol. Compared to placebo, exercise time after sublingual nitroglycerin increased 56% (P less than 0.001) initially and 51% (P less than 0.001) at retest. Compared to placebo, exercise time increased 58% (P less than 0.05) initially and 58% (P less than 0.005) at retest 1 hour after ISDN, 38% (P less than 0.05) initially and 27% (P less than 0.005) at retest 3 hours after ISDN, and 13% (NS) initially and 21% (P less than 0.02) at retest five hours after ISDN. The mean exericse times initially and at retest were not significantly different. Hemodynamic changes (decrease in systolic blood pressure and increase in heart rate) at 15 min persisted through 300 min after ISDN during both initial testing and during retesting. However, these changes were significantly less during retesting. We conclude that a partial tolerance to the hemodynamic effects of the drug develops after chronic use of high dose oral ISDN but that the antianginal efficacy of both sublingual nitroglycerin and oral ISDN is unimpaired.