Objective: This systematic review and meta-analyses provide an up-to-date synthesis on the effects of supplementation on circulating levels of toxic metabolites, markers of uremia and inflammation, blood lipids, and other clinical outcomes. Methods: Seventeen databases were searched, supplemented with internet and hand searching. Randomized controlled trials of adult end-stage renal-disease individuals receiving either hemodialysis or peritoneal dialysis were eligible. Trials were restricted to those which had administered a prebiotic, probiotic, or synbiotic as an oral supplement. Primary outcomes were measures of circulating endotoxin, indoxyl-sulphate, and p-cresyl sulfate. Results: Twenty-one trials were eligible (1152 randomized participants), of which 16 trials were considered to have a high risk of bias. The number of trials available for meta-analysis varied for each primary outcome. Synthesized data indicated that supplementation significantly reduced circulating levels of endotoxin (standardized mean difference, −0.61; 95% confidence interval, −1.03 to −0.20; P =.004; I2 = 0%), indoxyl-sulphate (−0.34; −0.64 to −0.04; P =.02; I2 = 0%), and p-cresyl sulfate (−0.34; −0.61 to −0.07; P =.01; I2 = 0%). For secondary outcomes, supplementation significantly reduced gastrointestinal symptoms (−0.54; −1.02 to −0.07; P =.02; I2 = 0%). Conclusions: Supplementation reduces toxic metabolites associated with cardiovascular disease and mortality in individuals receiving dialysis. However, the majority of trials included were low in quality.