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Abstract Whereas urinary creatinine excretion (UCE) is an established marker of muscle mass, both in critically ill and non-critically ill patients, analysis of urinary urea excretion (UUE) may allow estimation of proteolysis that is associated with critical illness. We evaluated the time courses of plasma urea and creatinine as well UUE and UCE in critically ill patients with a prolonged ICU stay. Our goal was to evaluate changes in plasma urea and creatinine in conjunction with their urinary excretion, to get a better understanding of urea handling in ICU patients. From 2002 to 2021, plasma urea and creatinine, UUE and UCE were determined in routinely obtained 24 h urine samples between ICU admission and day 30, in adult patients with an ICU-stay ≥ 28d. Urea-to-creatinine ratios in plasma and urine were calculated. Patients with stage 3 acute kidney injury (AKI) were excluded. Analyses were performed separately for females and males and for patients with and without acute renal failure to account for respectively differences in muscle mass and impaired renal function. Of 47,120 patients, who were admitted to the ICU between 2002 and 2021, 638 patients met the inclusion criteria. During the first 10 days mean ± SD plasma urea increased from 9.7 ± 6.0 mmol/L at ICU admission to 12.4 ± 7.9 mmol/L (P