In recent years, the increased interest in pediatric research has enforced the role of physiologically based pharmacokinetic (PBPK) models in pediatric drug development. However, an existing lack of published examples contributes to some uncertainties about the reliability of their predictions of oral drug exposure. Developing and validating pediatric PBPK models for oral drug application shall enrich our knowledge about their limitations and lead to a better use of the generated data. This study was conducted to investigate how whole-body PBPK models describe the oral pharmacokinetics of sotalol over the entire pediatric age. Two leading software tools for whole-body PBPK modeling: Simcyp® (Simcyp Ltd, Sheffield, UK) and PK-SIM® (Bayer Technology Services GmbH, Leverkusen, Germany), were used. Each PBPK model was first validated in adults before scaling to children. Model input parameters were collected from the literature and clinical data for 80 children were used to compare predicted and observed values. The results obtained by both models were comparable and gave an adequate description of sotalol pharmacokinetics in adults and in almost all pediatric age groups. Only in neonates, the mean ratio(Obs/Pred) for any PK parameter exceeded a twofold error range, 2.56 (95% confidence interval (CI), 2.10-3.49) and 2.15 (95% CI, 1.77-2.99) for area under the plasma concentration-time curve from the first to the last concentration point and maximal concentration (Cmax) using SIMCYP® and 2.37 (95% CI, 1.76-3.25) for time to reach Cmax using PK-SIM®. The two PBPK models evaluated in this study reflected properly the age-related pharmacokinetic changes and predicted adequately the oral sotalol exposure in children of different ages, except in neonates.