Infection and sepsis are a main cause of acute-on-chronic liver failure (ACLF). Besides bacteria, molds play a role. Voriconazole (VRC) is recommended but its pharmacokinetics (PK) may be altered by ACLF. Because ACLF patients often suffer from concomitant acute renal failure, we studied the PK of VRC in patients receiving continuous renal replacement therapy (RRT) with ACLF and compared it to PK of VRC in critically ill patients with RRT without concomitant liver failure (NLF). In this prospective cohort study, patients received weight-based VRC. Pre- and post-dialysis membrane, and dialysate samples obtained at different time points were analyzed by high-performance liquid chromatography. An integrated dialysis pharmacometric model was used to model the available PK data. The recommended, 50% lower, and 50% higher doses were analyzed by Monte-Carlo simulation (MCS) for day 1 and at steady-state with a target trough concentration (TC) of 0.5–3mg/L. Fifteen patients were included in this study. Of these, 6 patients suffered from ACLF. A two-compartment model with linear clearance described VRC PK. No difference for central (V1) or peripheral (V2) volumes of distribution or clearance could be demonstrated between the groups. V1 was 80.6L (95% confidence interval: 62.6–104) and V2 106L (65–166) with a body clearance of 4.7L/h (2.87–7.81) and RRT clearance of 1.46L/h (1.29–1.64). MCS showed TC below/within/above target of 10/74/16% on day 1 and 9/39/52% at steady-state for the recommended dose. A 50% lower dose resulted in 26/72/1% (day 1) and 17/64/19% at steady-state and 7/57/37% and 7/27/67% for a 50% higher dose. VRC pharmacokinetics are not significantly influenced by ACLF in critically ill patients who receive RRT. Maintenance dose should be adjusted in both groups. Due to the high interindividual variability, therapeutic drug monitoring seems inevitable.