Verapamil and nitroglycerin are widely used to prevent radial artery spasm (RAS) during percutaneous cardiovascular procedures. However, these agents are not typically available in most African countries and consequently, isosorbide dinitrate is often the only spasmolytic treatment. Our aim was to compare the efficacy of isosorbide dinitrate alone versus isosorbide dinitrate used together with nicardipine to prevent RAS during transradial coronary procedures. This was a randomized controlled double-blind multicenter trial. Patients (n=1,523) were randomized to receive either a sole therapy of isosorbide dinitrate (n=760) or the combination of isosorbide dinitrate and nicardipine (n=763). Our primary end point was the occurrence of RAS; defined as considerable perceived hindrance of catheter advancement. Our secondary end points were severe RAS; defined as (1) severe arm pain, (2) the need for either morphine or midazolam treatment, and (3) necessity for crossover to the contralateral radial or femoral artery. RAS incidence was reduced with the combination therapy versus isosorbide dinitrate alone (15% vs 25%, p <0.001), with a number needed to treat of 10 patients. There was also a significant reduction in the incidence of the secondary end points with combination therapy (3.6% vs 8.2%, p <0.001), with a number needed to treat of 22 patients. This result was driven by reductions in both femoral crossover (0.5% vs 2.4%, p=0.003) and the use of morphine or midazolam injections (1.6% vs 3.5%, p=0.02) with combination therapy. In conclusion, we demonstrated the superiority of the combination therapy of isosorbide dinitrate and nicardipine over isosorbide dinitrate alone in reducing the incidence of RAS.