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Abstract Background To assess the impact of attaining aggressive β-lactam (BL) pharmacokinetic-pharmacodynamic (PK/PD) targets on clinical efficacy in critically ill orthotopic liver transplant (OLT) recipients with documented early gram-negative infections. Methods The study prospectively enrolled OLT recipients admitted to the posttransplant intensive care unit between June 2021 and May 2024; they had documented gram-negative infections treated with targeted therapy continuous infusion (CI) BLs and underwent therapeutic drug monitoring (TDM)-guided BL dosing adjustment within the first 72 hours. Aggressive PK/PD target attainment was measured. Multivariate logistic regression analyses were performed to test independent variables associated with 30-day resistance occurrence. Results Fifty critically ill OLT recipients were treated with CI BL in monotherapy (n = 34) or combination (n = 16) therapy for documented gram-negative infections No significant difference in clinical/microbiological outcome emerged between monotherapy and combination therapy. In 4 patients (8.0%), resistance developed within 30 days. At multivariate analysis, failure in attaining an aggressive BL PK/PD target emerged as the only independent predictor of 30-day resistance development (odds ratio, 14.33 [95% confidence interval, 1.46–140.53]; P = .02). Conclusions Attaining an aggressive PK/PD target with CI BLs in critically ill OLT recipients with documented gram-negative infections could represent an effective strategy for minimizing resistance occurrence to the selected BL.