Fluconazole is frequently used for the treatment of invasive Candida infections in critically ill patients. However, alterations in renal functions might influence fluconazole clearance. Therefore, our objective was to study the impact of renal function on the population pharmacokinetics of fluconazole in critically ill patients with various degrees of renal function or undergoing continuous renal replacement therapy (CRRT). This was an open-label, multicenter observational study. Critically ill patients receiving fluconazole were included. Baseline and clinical data were collected. At days 3 and 7 of enrollment, blood samples were drawn for pharmacokinetic curves. Additionally, daily trough samples were taken. A nonlinear mixed-effects model was built, followed by Monte Carlo simulations for assessment of exposure to various dosages of fluconazole. Nineteen patients were included with a median age of 64.4 (range, 23 to 81) years and median weight of 82.0 (range, 44.0 to 119.5) kg. A linear two-compartment model best described fluconazole pharmacokinetics and demonstrated higher clearance than expected in critically ill patients. Simulations showed that daily dosages of 600 mg and 800 mg are needed for intensive care unit (ICU) patients with normal renal function and patients on CRRT, respectively, to achieve the EUCAST-recommended target fAUC (area under the concentration-time curve for the free, unbound fraction of the drug)/MIC ratio of 100. In conclusion, fluconazole clearance is highly variable in ICU patients and is strongly dependent on renal function and CRRT. Trough concentrations correlated well with the AUC, opening up opportunities for tailored dosing using therapeutic drug monitoring. We recommend doses of 400 mg for patients with poor to moderate renal function, 600 mg for patients with adequate renal function, and 800 mg for patients treated with CRRT. (This study has been registered at ClinicalTrials.gov under identifier NCT02666716.).