BACKGROUND: Travellers' diarrhoea affects tens of millions of people travelling to less developed countries or regions annually. There are positive reports of the use of rifaximin, a non-absorbed, gut-selective antibiotic to prevent travellers' diarrhoea. This study will critically review and analyse clinical trials on the subject. METHODS: Using the keywords [diarrhoea OR diarrhoea OR travel*] AND [rifaximin OR xifaxan OR xifaxanta OR normix OR rifagut], a preliminary search on the PubMed and Ovid databases yielded 411 papers published in English between 1 January 1988 and 1 July 2016. Of these, there were only five relevant clinical trials. RESULTS: The clinical trials were double-blind, placebo-controlled, randomized trials with a total of 879 subjects. The meta-analysis found significant reduction in risk of travellers' diarrhoea with rifaximin use compared to placebo (pooled RR 0.478, 95% CI: 0.375-0.610, and P  < 0.001). For the entire travel and follow-up period, the risk of developing travellers' diarrhoea was significantly greater in individuals receiving the placebo than those receiving rifaximin (daily doses of 400-600 mg). Overall, rifaximin offered significant protection rates of 48-72%, with lower protection rates for Asian than Latin American countries. In terms of tolerability, similar rates of adverse events were reported for the rifaximin and placebo group ( P  > 0.05), with no clinically significant or serious adverse events related to rifaximin use. CONCLUSIONS: There is good evidence supporting the use of rifaximin as a chemoprophylactic agent against travellers' diarrhoea, especially in individuals who are at high risk of severe complications from acute infectious diarrhoea. Rifaximin has an excellent tolerability/safety profile and demonstrated efficacy against diarrhoeagenic Escherichia coli and even enteroinvasive bacteria such Campylobacter species. Future studies should study the most effective dosing regimen for rifaximin chemoprophylaxis, as well as profile local antimicrobial resistance/susceptibility data in less developed regions to further guide rifaximin use.