Background: Severe hepatic failure (SHF) commonly leads to major changes in acid-base balance status. However, the direct effects of liver failure per se on acid base balance are poorly understood because this condition is usually associated with acute renal failure (ARF). Aim: To assess the effect of SHF on acid-base balance. Design: Retrospective laboratory investigation. Subjects: Thirty-seven critically ill patients with SHF complicated by ARF, and 42 patients with severe ARF without liver failure prior to renal replacement therapy. Intervention: Retrieval of clinical and laboratory data from prospective unit and laboratory databases. Methods: Quantitative acid-base assessment using Stewart-Figge methodology. Comparison of findings between the two groups. Comparison of demographic and clinical features. Results: Patients with combined SHF and ARF were younger and had significantly higher mean bilirubin, ALT and INR levels (p<0.0001). Their mean lactate concentration was higher (6.4 vs. 2.1 mmol/L; p<0.0001) leading to a greater anion gap (25.8 vs. 16.1 mmol/L; p<0.0001). The ionized calcium concentration (1.00 vs. 1.15 mmol/L; p<0.0001) was lower but the strong ion difference apparent (SIDa) was greater (42.0 vs. 38.0 mEq/L; p<0.005) due to hypochloremia. The albumin concentration was low but higher than in control patients (28 vs. 24 g/L; p<O.01) and the calculated strong ion gap (SIG) was greater (12.6 vs. 9.3 mEq/L; p<0.01). The base excess was similar to controls and the pH was preserved in the near normal range by marked hypocapnea. Conclusions: Combined SHF and ARF is a syndrome with unique acid-base changes due mostly to lactic metabolic acidosis and, in smaller part, to the accumulation of unmeasured anions. This acidosis, like that of ARF, is attenuated by hypoalbuminemia, by a unique preservation of the SIDa due to hypochloremia, and by marked hypocapnea.