Spontaneous bacterial peritonitis (SBP) heralds increased mortality in cirrhosis, mandating strategies for prophylaxis. Norfloxacin has been the recommended choice for SBP prevention. However, its use has raised concerns about antibiotic resistance. Rifaximin has been suggested as an alternative. We investigated the efficacy of rifaximin against norfloxacin in primary and secondary prophylaxis of SBP. In this open-labeled randomized trial, patients with either advanced cirrhosis having ascitic fluid protein levels (<1.5 g/l), Child-Pugh score ≥9 points, serum bilirubin ≥3 mg/dl or impaired renal function (primary prophylaxis group), or those with prior SBP (secondary prophylaxis group) received either norfloxacin (400 mg once daily) or rifaximin (550 mg twice daily). All patients were followed for six months, with the primary endpoint being the development of incident SBP. 142 patients were assessed for eligibility, of which 132 met the enrolment criteria; 12 were lost to follow-up, while 4 discontinued treatment. In patients on primary prophylaxis, occurrence of SBP was similar (14.3% vs. 24.3%, P = 0.5), whereas in secondary prophylaxis SBP recurrence was lower with rifaximin (7% vs. 39% P = 0.004). Rifaximin significantly reduced the odds for SBP development in secondary prophylaxis [OR (95% CI0.14 (0.02-0.73; P = 0.02)]. Patients receiving rifaximin as secondary prophylaxis also had fewer episodes of hepatic encephalopathy (23.1% vs. 51.5%, P = 0.02). 180-day survival between the arms in either group was similar (P = 0.5, P = 0.2). In comparison to norfloxacin, rifaximin significantly reduces incident events of SBP, as well as HE when used as a secondary prophylaxis, whereas for primary prophylaxis both have similar effects (NCT03695705). ClinicalTrials.gov number: NCT03695705.