A double-blind, controlled trial to study the efficacy of acidifying enemas of lactitol, a new galactoside-sorbitol disaccharide, and lactose vs. nonacidifying tapwater enemas was performed in 45 episodes of acute portal-systemic encephalopathy. At the time of randomization, all patients had encephalopathy of at least Grade 2+ severity, delay in the performance of number connection tests and hyperammonemia. A sequential analysis was performed which revealed after the inclusion of the first 20 patients, a significant failure of the non-acidifying enemas as compared to the lactitol enemas (p < 0.004). The tap-water enema group was, therefore, suspended but the rest of the study continued after rerandomization for lactose and lactitol groups. A favorable response to treatment was obtained in 19 (86%) of the patients receiving lactitol enemas and in 14 (78%) of those receiving lactose enemas. A similar significant improvement in portal-systemic encephalopathy parameters and index was observed after both treatments. Both types of acidifying enemas induced a significant pH decrease in stool (p < 0.05). These data suggest that acidifying agents like lactose and lactitol are effective and superior to tap-water enemas for the treatment of acute nitrogenous portal-systemic encephalopathy.