Background & Aims: Although renal failure is a common complication of sepsis and patients with cirrhosis frequently develop sepsis, there have been no studies specifically assessing renal function in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. The aim of this study was to investigate prospectively the frequency, characteristics, and outcome of renal failure in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis. Methods: One hundred six consecutive patients with cirrhosis and sepsis were studied prospectively. Patients with spontaneous bacterial peritonitis were excluded. Results: Twenty-nine out of 106 patients (27%) with cirrhosis and sepsis developed acute renal failure as compared with only 8 of 100 patients (8%) from a control group of cirrhotic patients without infection (P < .0001). Renal failure in the sepsis group was reversible in 22 (76%; 21% of all patients) patients and nonreversible in 7 (24%; 6% of all patients) patients. Renal failure was associated with impairment of effective arterial blood volume, without evidence of tubular damage. The occurrence and type of renal failure correlated strongly with mortality (mortality at 3 months: nonreversible renal failure, 100%; reversible renal failure, 55%; no renal failure, 13%). Among variables obtained at diagnosis of sepsis, the Model for End-Stage Liver Disease (MELD) score was the only independent predictive factor of mortality. Conclusions: Renal failure is common in patients with cirrhosis and sepsis unrelated to spontaneous bacterial peritonitis and is associated with arterial underfilling and renal vasoconstriction. Outcome is poor, even in the setting of reversible renal failure. The MELD score is the best prognostic marker of patients with cirrhosis and sepsis.