Propafenone is a new class Ic antiarrhythmic compound with a broad pharmacologic profile. In this study, its dose-response relationship was examined in a double-blind, randomized, placebo-controlled five treatment parallel design protocol. Patients enrolled had heart disease with Lown grade 2 premature ventricular contractions (PVCs) (greater than or equal to 30/hr) documented on 24-hour Holter recordings. Propafenone was compared in four doses (337.5, 450, 675, and 900 mg/day) to placebo. The double-blind phase lasted 2 weeks. Two hundred twenty-six patients were enrolled, of whom 171 were men and 55 were women; their mean age was 59.8 years and 85% were Caucasian and 4% were black. The arrhythmias were symptomatic in 173. Twenty (8.8%) withdrew from the study before completion: 15 had adverse reactions, two had intercurrent illnesses, and three withdrew for administrative reasons. In one patient, the density of arrhythmia appeared to increase with propafenone. Side effects were of central nervous system or gastrointestinal origin; less than 5% of patients developed first-degree atrioventricular block or intraventricular conduction defect. There were no deaths in the study. The occurrence of side effects was not related to dose. Propafenone had no effect on heart rate. It increased the PR interval at all doses (9% to 22% compared to placebo at baseline; p less than 0.01) at 450 to 900 mg/day after 2 weeks of therapy. The drug increased the QRS duration at all doses, highly significantly at 675 mg/day (8.5 msec; p less than 0.01) and at 900 mg/day (15.7 msec; p less than 0.01) after 2 weeks of therapy. Only at the highest dose was the QTc slightly but significantly (14.3 msec; p less than 0.01) increased. Propafenone exerted a dose-dependent effect on PVCs recorded on serial 24-hour Holter recordings: compared to placebo, at 2 weeks 337.5 mg/day reduced PVCs by 70.8% (p less than 0.05), 450 mg/day reduced PVCs by 82.0% (p less than 0.01), 675 mg/day reduced PVCs by 90.2% (p less than 0.01) and 900 mg/day reduced PVCs by 95.3% (p less than 0.01). The effects of the two highest doses of propafenone were significantly greater than those of 337.5 mg/day. In 68% of the patients receiving 900 mg/day, 80% or greater reduction in total PVCs was found. In addition, there was a greater than 90% decrease in ventricular couplets, and 96% decrease in ventricular tachycardia (VT) beats. Propafenone eliminated PVCs in 8% of all patients, ventricular couplets in 58%, and VT beats in 91%.(ABSTRACT TRUNCATED AT 400 WORDS)