The aim of the study is to compare the efficacy of flecainide, beta-blockers, sotalol, and verapamil in children with frequent PVCs, with or without asymptomatic VT. Frequent premature ventricular complexes (PVCs) and asymptomatic ventricular tachycardia (VT) in children with structurally normal hearts require anti-arrhythmic drug (AAD) therapy depending on the severity of symptoms or ventricular dysfunction; however, data on efficacy in children are scarce. Both symptomatic and asymptomatic children (≥ 1 year and < 18 years of age) with a PVC burden of 5% or more, with or without asymptomatic runs of VT, who had consecutive Holter recordings, were included in this retrospective multi-center study. The groups of patients receiving AAD therapy were compared to an untreated control group. A medication episode was defined as a timeframe in which the highest dosage at a fixed level of a single drug was used in a patient. A total of 35 children and 46 medication episodes were included, with an overall change in PVC burden on Holter of -4.4 percentage points, compared to -4.2 in the control group of 14 patients. The mean reduction in PVC burden was only significant in patients receiving flecainide (− 13.8 percentage points; N = 10; p = 0.032), compared to the control group and other groups receiving beta-blockers (− 1.7 percentage points; N = 18), sotalol (+ 1.0 percentage points; N = 7), or verapamil (− 3.9 percentage points; N = 11). The efficacy of anti-arrhythmic drug therapy on frequent PVCs or asymptomatic VTs in children is very limited. Only flecainide appears to be effective in lowering the PVC burden.