Background: A supplemental dose is often necessary after hemodialysis depending on the amount of drug removed by hemodialysis. However, there are different methods of estimating this amount, and most methods ignore drug rebound after hemodialysis. In this report we present a new area under the concentration curve (AUC)-based method that provides an estimate of the drug fraction removed by hemodialysis including drug rebound. Methods: Valganciclovir, the oral prodrug of ganciclovir, was administered to 6 patients with end-stage renal disease. Hemodialysis was performed after 32 h. The fraction of ganciclovir removed by hemodialysis was estimated using the new AUC-based method, a classical method (using the slope on and off hemodialysis), the back-extrapolation method, and a reference model (a two-compartment model with zero-order input and first-order elimination). Results: The AUC-based method and the back-extrapolation method provided accurate estimates of the fraction of ganciclovir removed by hemodialysis (47 ± 6 and 46 ± 5%, respectively) compared to the reference model (49 ± 3%). The classical method, which does not account for the rebound of ganciclovir concentrations after hemodialysis, overestimated the removed fraction by 9% (58 ± 3%). Conclusions: The new AUC-based method and the back-extrapolation method accurately estimate the drug fraction removed by hemodialysis for drugs with a rebound after hemodialysis. The AUC-based method is more robust and as efficient compared to the back-extrapolation method.