Studies on animal models of hepatic encephalopathy (HE) suggest that poor nutritional status may facilitate the development of HE. Insulin resistance and diabetes mellitus have recently been reported to affect cognition in patients with hepatitis C cirrhosis awaiting liver transplantation. Our aim was to investigate the effects of malnutrition and diabetes mellitus on HE in unselected patients with liver cirrhosis. A total of 128 consecutive cirrhotic patients were prospectively evaluated for the presence of HE according to the West-Haven criteria as well as by means of two psychometric tests and fasting plasma ammonium ion concentrations. Nutritional status was assessed by anthropometry and estimation of recent weight change. Fasting plasma glucose was measured, and in a subgroup of 84 patients fasting serum insulin and insulin resistance were also determined. Fifty-one (40%) cirrhotics were malnourished, 33 (26%) had diabetes and 42 (34%) had HE. Patients with vs. without malnutrition had more frequently HE (46 vs. 27%; P=0.031) but did not differ in age, aetiology or severity of liver cirrhosis (P>0.1). Multivariate analysis showed that the time needed to perform number connection test A was independently correlated to age, the Child-Pugh score, diabetes and malnutrition (P<0.05 for all). Plasma ammonium ion levels were related to insulin resistance (r=0.42, P<0.001) and muscle mass (r=0.28, P=0.003). Malnutrition and diabetes mellitus seem to be related to HE in patients with liver cirrhosis. Nutritional status and insulin resistance might be implicated in the pathogenesis of HE.