Background: Mibefradil, a newly approved antihypertensive and antianginal drug, is the first member of a new class of calcium antagonists (CAs), the tetralol derivatives, that selectively blocks T-type Ca2+ channels in contrast to classical CAs which, at therapeutic concentrations, block only L-type Ca2+ channels. Since patients with chronic stable angina pectoris typically may be treated with the combination of a long-acting nitrate and a CA, the additive efficacy and safety of mibefradil in combination with nitrate therapy needs to be determined. Hypothesis: This study was designed to assess the efficacy, tolerability, and safety of mibefradil when added to long-acting nitrate therapy in patients with chronic stable angina pectoris. Methods: Following a 1-week placebo run-in period, patients were randomized to receive either mibefradil 50 mg (n = 96) or placebo (n = 93) once daily in addition to their nitrate therapy. After 2 weeks of active treatment, patients receiving the mibefradil were force titrated to 150 mg once daily for an additional 2 weeks. Exercise tolerance tests (ETTs) were performed at the end of weeks 2 and 4; patients also maintained an anginal diary during the 4-week treatment period. Results: After 2 weeks of treatment with 50 mg mibefradil (within the current recommended dose range), a statistically significant but modest increase in total exercise duration was observed (treatment effect 16.4 s, p = 0.04). Similarly, there was a significant increase in time to onset of ischemia (treatment effect 26 s, p = 0.008). The adverse event profile of the 50 mg dose was indistinguishable from placebo, indicating that this dose was extremely well tolerated. At week 4, the mibefradil-treated patients were taking 150 mg, which is above the current recommended dose range. The increase in total exercise duration was larger for the mibefradil 150 mg group than for the placebo group. For the intent-to-treat population, this difference did not reach statistical significance, whereas in the standard population it did (treatment effect 21 s, p = 0.05). The other two ETT variables, time to onset of angina and time to onset of 1 mm ST-segment depression, demonstrated significantly greater effect with mibefradil 150 mg (treatment effects 40 s, p = 0.002, and 55 s, p < 0.001, respectively, for the intent-to-treat population). Mibefradil 150 mg was associated with more adverse events than placebo, specifically, dizziness, leg edema, and postural hypotension. Conclusions: This study demonstrates that mibefradil 50 mg once daily in the setting of the background long-acting nitrate therapy produces additive antianginal and anti-ischemic effects and is extremely well tolerated.