Background and Objectives: Indoxyl sulfate (IS) is a major uraemic toxin contributing to major cardiovascular morbidity and mortality. The aim of our study was to evaluate whether synbiotic (pre- and probiotic) therapy alters the gut microbiota and reduces serum concentrations of IS in hemodialysis patients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: 80 ESRD patients undergoing regular hemodialysis recruited (between January, 2017 and March, 2017) to a single-blind, placebo-controlled trial of synbiotic therapy over 6 weeks. The primary outcome was serum Indoxyl Sulfate (IS). Secondary outcomes included serum Creatinine, Blood Urea Nitrogen (BUN), Sodium, Potassium, Calcium, Phoshorus and C-reactive protein (CRP). Results: All 80 individuals randomized (70% males) completed the study. Synbiotic therapy significantly reduced serum IS (change in serum IS is 13.55 ± 9.31 in the group receiving Synbiotics, in comparison to 3.18 ± 14.56 in the control group, p-values:<0.001, 0.176 respectively ). Also Synbiotic therapy significantly reduced the levels of Creatinine, BUN, Phosphorus (p-values <0.001) and CRP (p-values: 0.011). Conclusion: In Haemodialysis patients, synbiotics significantly reduced serum IS, besides a marked reduction in serum Phosphorus and CRP without recorded adverse effects.