Following the development of digoxin radioimmunoassay, we noted that serum digoxin concentrations appeared to rise in patients given quinidine. To further evaluate this important possible interaction between digoxin and quinidine, charts from 863 cardiology patients were reviewed. Ninety two patients received both drugs after having been on digoxin alone; 38 were ineligible for the study because of insufficient data and 27 were excluded because of changing renal function and/or concomitant antiarrhythmic drug therapy, leaving 27. Serum digoxin increased in 25 of the 27 study patients (93%) during quinidine therapy; mean serum digoxin rose from 1.4 ng/ml before quinidine to 3.2 ng/ml during quinidine. Anorexia, nausea and/or vomiting developed in 16 patients (59%) during quinidine therapy, but disappeared in all 10 patients in whom digoxin alone was reduced in dose, suggesting that digoxin had a causative role in the appearance of these symptoms although they developed only after quinidine had begun. Three of thirteen patients with only atrial arrhythmias on digoxin prior to quinidine developed new ventricular premature depolarizations (VPD) after starting quinidine; two of these three as well as four patients with prior VPDs developed new ventricular tachycardia, ventricular fibrillation, asystole, or sudden death. When starting quinidine in patients who are taking digoxin, the clinical course, ECG and serum digoxin should be followed closely.