Cefepime (FEP) is used for hospital- and ventilator-associated pneumonia when is involved. However, its pharmacokinetics (PK) in severe pneumonia necessitating extracorporeal membrane oxygenation (ECMO) remain unclear. This single-center, prospective study enrolled 70 mechanically ventilated patients with suspected pneumonia ( = 9 on ECMO), excluding those on renal replacement therapy. Dosing followed institutional renal function-based protocols. Plasma concentrations were quantified by liquid chromatography-tandem mass spectrometry, and a two-compartment PK model was developed using for R, with volume of distribution (Vd) scaled to body weight and ECMO status, and clearance (CL) scaled to renal function. Target attainment was calculated from Bayesian posterior predictions, and Monte Carlo simulations evaluated the cumulative fraction of response (CFR) for regimens of 2 g IV every 8 h, administered as either 0.5 h intermittent or 4 h extended infusion with or without a 2 or 3 g loading dose (LD) (0.5 h). Success was defined as achieving 100% T within 24 h for 80% of isolates. Seventy patients (60% male, = 9 ECMO) contributed 114 plasma samples (1-14 per patient). The model fit the data well. ECMO was associated with a 2.8-fold increase in Vd without altering CL. Monte Carlo simulations demonstrated that standard dosing without an LD failed to achieve CFR ≥ 80% in ECMO patients. Incorporating a 3 g but not 2 g LD restored CFR to ≥80% in ECMO. ECMO significantly increased FEP Vd in intensive care unit patients, suggesting sub-optimal target attainment at higher minimum inhibitory concentrations. A 3 g LD appears essential for target attainment, underscoring the need for revised dosing strategies in ECMO.