Background <p>Patients with decompensated cirrhosis have high prevalence of frailty that increases morbidity and mortality. This study was done to determine the impact of six months of Rifaximin therapy on frailty in patients with decompensated cirrhosis.</p> Methods <p>100 patients with frailty as assessed by Liver frailty Index (LFI &gt; 4.5) at baseline were randomized 1:1 to receive standard medical therapy (SMT) plus Rifaximin (rSMT, intervention) versus SMT (control) alone. The primary outcome was an improvement in frailty at 6&#xa0;months. Secondary outcome measures included improvement in CTP and MELD, inflammatory markers, hospitalization, and survival.</p> Results <p>Frailty improved significantly in the intervention arm as compared to the control arm (4.7(4.5–5.0) to 4.2(4.1–4.5), (<i>P</i> &lt; <i>0.00</i>) vs 4.7(4.6–5.0) to 4.7(4.4–5.2),<i> (P</i> = <i>0.70)</i> at 6&#xa0;months. The disease severity as assessed by CTP and MELD, scores showed a significant improvement in the rSMT group as compared to the SMT group (<i>P</i> &lt; <i>0.05</i>). The delta change in MELD score was −2.3 ± 2.9 versus 1.7 ± 5.4 (<i>P</i> &lt; <i>0.00</i>) in the intervention arm as compared to control arm. Inflammatory markers showed significant improvement, with a higher delta change in IL-6 in the intervention arm (-10 [-15.7/-4.4] vs -5 [-10.2/-0.5]; <i>P</i> = <i>0.01</i>). The patients in rSMT arm had lesser number of hospitalizations 8(16%) vs 26(52%); <i>P</i> &lt; <i>0.00</i>) over the course of 6&#xa0;months. The mortality in rSMT and SMT arms was 10% (n = 5), and 22% (n = 11), respectively though there was no significant difference in the overall survival (<i>P</i> = <i>0.11</i>).</p> Conclusion <p>Rifaximin therapy in decompensated cirrhosis has a significant impact on improving frailty and disease severity, with a reduction in hospitalization rate.</p> Clinical Trial Registry Number <p>CTRI/2023/01/048824</p> Graphical Abstract <p></p>