Hepatic encephalopathy (HE) describes a wide spectrum of often-reversible neuropsychiatric abnormalities that occur in patients with acute or chronic liver disease. Currently, the mainstay treatment of HE includes; non-absorbed disaccharides (like lactulose) and non-absorbable antibiotics (ex. rifaximin). Metronidazole is one of the alternative treatment options for acute HE. Thus we performed open label randomized controlled trial to compare efficacy of rifaximin and metronidazole. This is an open label randomized controlled trial in which cirrhotic patients irrespective of etiology was enrolled. The symptoms of HE were graded according to West Haven Criteria (WHC) at baseline and after 7 days of treatment. Patients were allocated in two groups; Rifa and Metro groups, and were subjected to rifaximin and metronidazole respectively in addition to lactulose. Treatment efficacy and adverse affects in both the groups were calculated. Total 120 subjects with HE (grade- III or IV) were selected, 60 subjects were subdivided into each group. Out of 60 subjects of Rifa group, efficacy of treatment was noted in 14 (23.33%) patients and out of 60 subjects of Metro Group, treatment was found effective in 45 (75%) patients with p value of 0.0001. The conclusion of this study is that efficacy of metronidazole is superior to rifaximin in managing acute episode of hepatic encephalopathy due to decompensated liver cirrhosis. Hence, its use is recommend in poor resource settings, because of its lower cost and good safety margin.