Despite steady progress in therapeutics of liver disease, portal systemic encephalopathy remains to be a great challenge for clinicians because of the heterogeneity of neuropsychiatric symptoms, multiple risk factors and complexity on achieving a sustained response. We aimed to evaluate the efficacy of L-Ornithin, L-Aspartate versus lactulose in Mexican patients with hyperammonemic hepatic encephalopathy. A total of 20 patients were randomly allocated to receive either lactulose(n = 10) or L-ornithine - L-aspartate (n = 10) for 2 weeks. At baseline, patients of both groups were comparable in age (64 +/- 7 versus 60 +/- 6) and degree of hepatic failure according to the Child-Pugh scale (9.2 +/- 1.3 versus 9.2 +/- 1.1). A significant decrease in ammonia levels was observed both in the lactulose group (120.4 +/- 8.1 versus 91.4 +/- 10, p < 0.05) and in the LOLA group (141.6 +/- 9.1 versus 96.9 +/- 9.3, p < 0.05). Moreover, in patients who received LOLA a significant improvement was observed in mental status (1.0 +/- 0.14 versus 0.4 +/- 0.16, p < 0.05), Number Connection Test (184 +/- 43 versus 88 +/- 7, p < 0.05), asterixis (14.6 +/- 2.8 versus 6.7 +/- 1.5, p < 0.05), as well as EEG findings (6.8 +/- 0.6 versus 8.1 +/- 0.2 cycles per second, p < 0.05). Compliance with study medications was similar between the lactulose group (94%) and the LOLA group (100%). No serious adverse events were reported in the two groups; however, in the lactulose group an increase in the number of weekly defecations was reported, as well as a higher incidence of abdominal pain or flatulence. Finally, both patient groups reported an improvement in the Visual Analogue Scale for EuroQol index (51.1 +/- 24.1 versus 61.5 +/- 15.8, p < 0.05, in the lactulose group; 56.5 +/- 24.5 versus 70 +/- 19.4, p < 0.05, in the LOLA group). In conclusion, oral administration of lactulose or L-ornithine - L-aspartate to Mexican patients with cirrhosis and hyperammonemic encephalopathy significantly reduced serum ammonia levels in study groups and additionally improved mental status parameters, number connection test, asterixis scores, and EEG activity in the group receiving L-ornithine-L-aspartate.