The effectiveness of an intermittent regimen of transdermal nitroglycerin in chronic stable angina was evaluated in 206 patients using serial treadmill testing. After a placebo stabilization phase, patients were randomized to 4 weeks of double-blind treatment with transdermal nitroglycerin, 10 or 20 cm2 (equivalent to 5 or 10 mg/24 h) (Group A); transdermal nitroglycerin, 30 or 40 cm2 (equivalent to 15 or 20 mg/24 h) (Group B), or placebo. Patches were applied at 8:00 AM and removed at 8:00 PM each day throughout the study. Treadmill testing was performed 0, 4, 8 and 12 h after patch application at baseline (day 0) and on days 1, 15 and 29. After short-term application of the transdermal patches, treadmill walking time was greater for patients in both Group A and Group B than for the placebo group at all time points tested; differences from placebo were statistically significant at 12 h for Group A and at 4, 8 and 12 h for Group B. After 2 and 4 weeks of long-term therapy, treadmill walking time was again greater for Group B than for the placebo group at all postapplication time points; differences from placebo reached statistical significance at 4 h (2 weeks) and 8 h (2 and 4 weeks). The improvement in the treadmill walking time seen over the short-term in Group A was largely lost after 4 weeks of long-term therapy. Potentially important differences in the patient characteristics of the two active treatment groups, particularly the greater use of a beta-adrenergic blocker among patients in Group A, may have contributed to these observed differences in treatment effect. An unexpected finding was the ability of the placebo group to exercise longer than either active treatment group just before patch application during long-term therapy; nonetheless, absolute responsiveness to transdermal nitroglycerin after patch application remained virtually unchanged in both active treatment groups during the 4 week treatment period. Intermittent transdermal nitroglycerin therapy was well tolerated in the vast majority of patients; nine patients experienced an increase in nonexertional angina during the patch-off periods but completed the study uneventfully.