Serum creatinine concentration is commonly used in conjunction with individual patient characteristics (e.g., age, sex, and body weight) in order to estimate creatinine clearance. Such estimates of creatinine clearance are widely used as a parameter for individualization of dosages of drugs excreted primarily via the kidneys in patients with diminished renal function. However, estimation of creatinine clearance in patients with concurrent hepatic disease tends to result in substantial overprediction of observed creatinine clearance in this patient population. This report suggests that a diminished rate of creatinine production in patients with hepatic disease is a likely explanation for this anomaly. This postulated mechanism is based on a presentation of the biology of creatinine formation.