Background: Icodextrin enhances peritoneal filtration for patients on peritoneal dialysis (PD). However, clinically important outcomes have not yet been analyzed using authentic, objective statistical methods. The present systematic review aimed to determine the risks and benefits of icodextrin compared with a glucose-based solution with respect to clinically important and patient-centered outcomes. Methods: We systematically investigated only randomized controlled trials (RCTs) by adopting the Cochrane Database of Systematic Review (2014) and searched the CENTRAL, MEDLINE, and EMBASE databases for eligible studies reported in the literature. The quality of the evidence was assessed using the GRADE approach. Results: We finally evaluated important outcomes in 13 RCTs. Icodextrin significantly decreased the number of reported episodes of uncontrolled fluid overload in four RCTs that involved 236 patients (relative risk [RR], 0.31; 95% confidence interval [CI], 0.12 to 0.82; moderate certainty evidence). However, the inclusion of icodextrin for peritoneal ultrafiltration did not significantly differ in six RCTs involving 252 patients (mean difference [MD], 186.76 mL; 95% CI, − 47.08 to 420.59; low certainty evidence). Regarding other clinically important outcomes, all-cause mortality in 10 RCTs involving 1106 patients (RR, 0.75; 95% CI, 0.33 to 1.71; low certainty evidence) and technical survival in five RCTs involving 470 patients (RR, 0.57; 95%CI, 0.29 to 1.12; low certainty evidence) were not significant. Urine volume in four RCTs involving 136 patients, residual renal function in five RCTs involving 181 patients and peritoneal function measured as the ratio of solute concentration in dialysate and plasma (D/P ratio) in two RCTs involving 105 patients were not specifically affected by icodextrin, and the results for adverse events were similar between icodextrin and glucose PD solutions. Conclusion: Icodextrin could relieve uncontrolled fluid overload without adding risk. However, a significant effect on clinically relevant outcomes such as technical survival and overall patient survival was not suggested. More trials are required to increase the statistical power and to verify the value of icodextrin in clinical practice.