To find out whether the changes in the brain histaminergic system are involved in the pathophysiology of portal-systemic encephalopathy, we examined the effects of histamine H1 receptor blockade on spontaneous locomotor activity, feeding, and circadian rhythmicity in rats with portacaval anastomosis (PCA). Pyrilamine, an H1 receptor blocker (15 mg/kg/day), was delivered with osmotic minipumps. Spontaneous locomotor activity was recorded for 72 hours in the open-field with an electromagnetic detector. Food intake was monitored twice daily at the end of the light (7 PM) and the dark (7 AM) phases for 3 days. Histamine H1 receptor density in the suprachiasmatic nucleus (SCN) was examined with receptor autoradiography, employing [3H]pyrilamine. PCA surgery led to decreased movement time and velocity and flattened amplitude of the circadian rhythms of locomotion and feeding. In sham-operated rats, pyrilamine significantly decreased the movement time and velocity, as well as the total food consumption and completely abolished the circadian rhythmicity of locomotion. In contrast, pyrilamine increased the movement time and velocity in PCA-operated rats, particularly in the dark phase, and improved the precision of the circadian rhythms of locomotion and feeding. Histamine H1 receptor density was not altered by PCA surgery, whereas pyrilamine treatment led to the complete blockade of H1 receptors in both sham- and PCA-operated rats. We suggest that histaminergic imbalance has contributed to the generation and maintenance of the decreased spontaneous locomotor activity and altered circadian rhythmicity following PCA surgery in the rat, probably via an H1 receptor–mediated mechanism.