Eighteen patients (2 females, 16 males) with coronary artery disease and a positive bicycle exercise test were treated with 50 mg slow-release isosorbide-5-mononitrate (ISMN SR) once daily, 20 mg nifedipine SR twice daily and a combination of both drugs during 2 weeks in a randomized double-blind sequence. Fifteen patients completed the study. The efficacy of each therapy was assessed by ECG stress testing after each treatment period. Both substances were equally effective in the reduction of ischemic ST depression: 0.40 ± 0.22 mV with placebo, 0.31 ± 0.16 mV during nifedipine SR and 0.31 ± 0.29 mV during ISMN SR, 0.28 ± 0.21 mV during the combination. However, during monotherapy with either nifedipine SR or ISMN SR 6 patients did not improve. The alternative monotherapy was effective in 3 out of 6 patients. Combination treatment gave further advantage only to one third of the patients. We conclude that both nifedipine and ISMN in slow-release formulations are equally effective in the treatment of myocardial ischemia. In the individual patient, however, therapy failure may occur. These patients should be switched to another monotherapy. If both monotherapies are ineffective, combination treatment should be considered.