BACKGROUND Atrial fibrillation (AF) with excessively high ventricular rates (VR) occurs in dogs with advanced heart disease. Rate control improves clinical signs in these patients. Optimal drug therapy and target VR remain poorly defined. OBJECTIVE Digoxin-diltiazem combination therapy reduces VR more than either drug alone in dogs with high VR AF. METHODS Eighteen client-owned dogs (>15 kg) with advanced heart disease, AF, and average VR on 24-hour Holter > 140 beats per minute (bpm). METHODS After baseline Holter recording, dogs were randomized to digoxin or diltiazem monotherapy, or combination therapy. Repeat Holter evaluation was obtained after 2 weeks; dogs were then crossed over to the other arm (monotherapy or combination therapy) for 2 weeks and a third Holter was acquired. Twenty-four hour average VR, absolute and relative VR changes from baseline, and percent time spent within prespecified VR ranges (>140, 100-140, and <100 bpm) were compared. Correlations between serum drug concentrations and VR were examined. RESULTS Digoxin (median, 164 bpm) and diltiazem (median, 158 bpm) decreased VR from baseline (median, 194 bpm) less than the digoxin-diltiazem combination (median, 126 bpm) (P < .008 for each comparison). With digoxin-diltiazem, VR remained <140 bpm for 85% of the recording period, but remained >140 bpm for 88% of the recording period with either monotherapy. Serum drug concentrations did not correlate with VR. CONCLUSIONS At the dosages used in this study, digoxin-diltiazem combination therapy provided a greater rate control than either drug alone in dogs with AF.