We evaluated the efficacy and the safety of medium- (240 mg/day) and high-dose (360 mg/day) diltiazem alone and in combination with digoxin when used for control of heart rate in 12 patients with chronic atrial fibrillation. Medium-dose diltiazem was comparable to therapeutic dose of digoxin at rest (88 ± 19 vs 86 + 12 beats/min) but superior during peak exercise (154 23 vs 170 + 20 beats/min; p < .05). High-dose diltiazem resulted in better control of heart rate than digoxin both at rest (79 17 beats/min; p < .05) and exercise (136 + 25 beats/min; p < .05) but was associated with side effects in 75% of the patients. Combined therapy of digoxin and diltiazem enhanced the effect of digoxin alone and resulted in significantly better control of heart rate at rest (67 + 16 beats/min with medium-dose and 65 + 15 beats/min with high-dose diltiazem) and during peak exercise (132 + 32 and 121 ± 24 beats/min, respectively). However, the difference in heart rate between these two doses was not significant. Reduction of heart rate combined with concomitant effect on blood pressure 0resulted in a significant fall in pressure-rate product at rest from 10,077 + 1708 mm Hg/min on digoxin alone to 7877 + 1818 mm Hg/min after the addition of medium-dose diltiazem (p < .05) and during exercise from 25,670 + 3606 to 18,439 4115 mm Hg/min (p < .05). Continued therapy with digoxin combined with diltiazem 240 mg/day for 21 ± 8 days in nine patients showed persistent effect on heart rate and blood pressure without any toxic manifestations or change in serum digoxin (1.5 + 0.4 vs 1.3 + 0.4 ng/ml) or plasma diltiazem concentrations (204 72 vs 232 129 ng/ml). In conclusion, medium-dose diltiazem when combined with digoxin is an effective and safe regimen for the treatment of patients with chronic atrial fibrillation and enhances digoxin-mediated control of heart rate both at rest and during exercise.