Background By inhibiting the growth of pathogenic bacteria and modulating the local intestinal immune system, probiotics may reduce bacterial translocation and systemic endotoxaemia, factors partially responsible for post‐operative complications following liver resection for hepatocellular carcinoma in patients with cirrhosis. Methods Patients with resectable hepatocellular carcinoma developed in the setting of chronic liver disease were prospectively divided into two equal‐sized groups: one receiving probiotic treatment 14 days prior to surgery and the other receiving placebo. The primary endpoint was the level of circulating endotoxins after hepatectomy. Secondary endpoints were systemic inflammation (inflammatory cytokine levels), post‐operative liver function and overall post‐operative complication rate. Results From May 2013 to December 2018, 64 patients were randomized, and 54 patients were included in the analysis, 27 in each arm. No significant change in endotoxin levels was observed over time in either group (P = 0.299). No difference between the groups in terms of post‐operative liver function and overall complication rates was observed. The only differences observed were significant increases in the levels of TNFalpha (P = 0.019) and interleukin 1‐b (P = 0.028) in the probiotic group in the post‐operative period. Conclusion Contrary to the modest data reported in the literature, the administration of probiotics before minor liver resection for hepatocellular carcinoma developed in the setting of compensated chronic liver disease does not seem to have an impact on circulating endotoxin levels or post‐operative complication rates. Trial registration Trial registration: NCT02021253.