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Introduction: Quinolone prophylaxis is recommended for patients with advanced cirrhosis at high risk of spontaneous bacterial peritonitis (SBP) or with prior SBP. Yet, the impact of long-term antibiotic prophylaxis on the microbiome of these patients is poorly characterized., Methods: Patients with liver cirrhosis receiving long-term quinolone prophylaxis to prevent SBP were prospectively included and sputum and stool samples were obtained at baseline, 1, 4 and 12 weeks thereafter. Both bacterial DNA and RNA were assessed with 16S rRNA sequencing. Relative abundance, alpha and beta diversity were calculated and correlated with clinical outcome., Results: Overall, 35 stool and 19 sputum samples were obtained from 11 patients. Two patients died (day 9 and 12) all others were followed for 180 days. Reduction of Shannon diversity and bacterial richness was insignificant after initiation of quinolone prophylaxis (p > 0.05). Gut microbiota were significantly different between patients (p < 0.001) but non-significantly altered between the different time points before and after initiation of antibiotic prophylaxis (p > 0.05). A high relative abundance of Enterobacteriaceae > 20% during quinolone prophylaxis was found in three patients. Specific clinical scenarios (development of secondary infections during antibiotic prophylaxis or the detection of multidrug-resistant Enterobacteriaceae ) characterized these patients. Sputum microbiota were not significantly altered in individuals during prophylaxis., Conclusion: The present exploratory study with small sample size showed that inter-individual differences in diversity of gut microbiota were high at baseline, yet quinolone prophylaxis had only a moderate impact. High relative abundances of Enterobacteriaceae during follow-up might indicate failure of or non-adherence to quinolone prophylaxis. However, our results may not be clinically significant given the limitations of the study and therefore future studies are needed to further investigate this phenomenon., Competing Interests: Competing interestsMMM: Speaking fees from AbbVie and Alnylam, travel support from AbbVie, Gilead and Intercept, all unrelated to the submitted work. The study was supported by a research grant from Gilead to MMM as a part of the “Förderprogramm Infektiologie 2017”. VTM: Travel support from AbbVie and Gilead unrelated to the submitted work. KS: Travel support from AbbVie unrelated to the submitted work. SZ: Speaking and/or consulting fees from AbbVie, Bristol-Myers Squibb, Falk, Gilead, Janssen, and Merck/MSD all unrelated to the submitted work. CML: Speaker fees from AbbVie, Gilead, MSD, Norgine and travel support from AbbVie, and Gilead, all unrelated to the submitted work. SR, AM, JK, and RS declare that they have no competing interests., (© The Author(s) 2020.)