We studied the long-term antianginal and anti-ischemic effects of two dosage regimens designed to prevent tolerance to transdermal nitroglycerin (TNTG): (1) 10 mg TNTG applied for 16 h with a ‘nitrate-free’ interval of 8 h; (2) 10 mg TNTG applied for 16 h followed by a ‘nitrate-low’ interval of 5 mg applied for 8 h. 129 patients completing a 3-month study period were evaluated by repeated exercise tests. Both regimens significantly increased maximum exercise duration at 3 months, from 699.1 ± 23.4 to 833 ± 21.9 s and from 686.1 ± 20 to 789.6 ± 22.6 s, respectively, reduced the number of patients with 1 mm S-T segment depression and increased the time duration to 1 mm S-T segment depression. Marked reductions in anginal attacks was observed in both groups: from 6.5 to 0.15 attacks per week and from 6.0 to 0.15 attacks per week, respectively. No statistically significant differences were found between the groups, and both regimens were well tolerated. In conclusion, our results demonstrate sustained antianginal efficacy, without tolerance, of either ‘nitrate-free’ of ‘nitrate-low’ interval therapy with transdermal nitroglycerin.