Fourteen patients (four females) with chronic atrial fibrillation were entered into a randomized, double-blind crossover study to compare the effects of treatment with diltiazem alone, digoxin alone, and a combination of diltiazem plus digoxin. The dose of digoxin was adjusted so as to achieve serum concentrations within the range 1.3–2.6 nmoll−1 between six and eight hours after dosing. Four patients were withdrawn from the study; three patients experienced side effects while taking diltiazem and one reverted to sinus rhythm while taking digoxin. Among the remaining 10 patients, mean heart rates were significantly lower during treatment with the combination of digoxin and diltiazem than with digoxin alone both at rest, after exercise and during ambulatory ECG monitoring. Post-exercise heart rates were reduced by 15% with combination therapy when compared with digoxin alone (151.9 vs. 128.1 bpm), but there was no evidence that this reduction in ventricular rate was associated with improved exercise tolerance. The results suggest that further reduction of the rapid ventricular rates seen in digitalized patients with AF by the use of diltiazem does not appear to be of benefit in the majority of patients.