β-Lactams are routinely used as empirical therapy in critical illness, with extended concentrations above the minimum inhibitory concentration (MIC) of the infecting organism required for effective treatment. Changes in renal function in this setting can significantly impact the probability of achieving such targets. Analysis was made of trough plasma drug concentrations obtained via therapeutic drug monitoring, compared with renal function, in critically ill patients receiving empirical β-lactam therapy. Drug concentrations were measured by means of high-performance liquid chromatography and corrected for protein binding. Therapeutic levels were defined as greater than or equal to MIC and greater than or equal to four times MIC (maximum bacterial eradication), respectively. Renal function was assessed by means of an 8-h creatinine clearance (CLCR). Fifty-two concurrent trough concentrations and CLCR measures were used in analysis. Piperacillin was the most frequent β-lactam prescribed (48%), whereas empirical cover and Staphylococcus species were the most common indications for therapy (62%). Most patients were mechanically ventilated on the day of study (85%), although only 25% were receiving vasopressors. In only 58% (n = 30) was the trough drug concentration greater than or equal to MIC, falling to 31% (n = 16) when using four times MIC as the target. CLCR values ≥ 130 mL/min/1.73 m2 were associated with trough concentrations less than MIC in 82% (P < .001) and less than four times MIC in 72% (P < .001). CLCR remained a significant predictor of subtherapeutic concentrations in multivariate analysis. Elevated CLCR appears to be an important predictor of subtherapeutic β-lactam concentrations and suggests an important role in identifying such patients in the ICU.