Abstract Background and Aims In many patients on chronic hemodialysis, interdialytic weight gain (IDWG) is greater than 4.0%-4.5% of dry weight, the value recommended by the international guidelines. High IDWG is a condition associated with risk of all-cause mortality and hospitalization and it depends on elevate intake of fluids and/or foods. More specifically, high intake of water is secondary to the disturbing and constant presence of thirst in such patients, so the limitation of the IDWG is a challenge both for the patients and the physicians. Low dialysate sodium levels can significantly reduce thirst as well as the water intake in the interdialytic period because they can increase the removal of sodium during the dialytic session, and this leads to a reduced content of sodium in the body. The present systematic review and meta-analysis aims at evaluating the efficacy of low dialysate sodium concentration on interdialytic weight gain (IDWG) in chronic hemodialysis patients. Method Studies were eligible for inclusion if they were English language papers published in a peer-reviewed journal and met the following inclusion criteria: 1) Primary research studies in adult patients (over 18 years of age), 2) Included patients with end-stage renal disease on chronic hemodialysis since at least 6 months; 3) Compared standard (138-140 mmol/l) or high (>140 mmol/l) dialysate sodium concentration with low (<138 mmol/l) dialysate sodium concentration; 4) Included one outcome of interest: interdialytic weight gain. We excluded studies on pediatric patients, pre-dialysis CKD patients, acute kidney injury patients, ESRD patients with other renal replacement therapy modalities such as peritoneal dialysis and transplant. Medline, PubMed, Web of Science, and the Cochrane Library were searched for studies comparing low or high dialysate sodium concentration. Outcome of interest was IDWG. The quality of reporting for each study was performed using the Quality Assessment Tool of Controlled Intervention Studies of the National Institutes of Health. The quality of reporting of each cross-over study was performed using the Revised Cochrane Risk of Bias (RoB) tool for cross-over trials as proposed by Ding et al. Results Nineteen studies (710 patients) were included in the analysis: 15 were cross-over and 4 parallel randomized controlled studies. In cross-over studies, pooled analysis revealed that dialysate sodium concentration reduced IDWG with a pooled MD of −0.40 kg (95% CI -0.50 to −0.30; P < 0.00001). The systematic review of four parallel, randomized, studies revealed that the use of a low dialysate sodium concentration was associated with a significant reduction of the IDWG in two studies, sustained and almost significant (P=0.05) reduction in one study, and not significant reduction in one study. In most studies, the frequency of intradialytic hypotensive events did not differ significantly between low and high sodium dialysate hemodialysis. The GRADE methodology was used to assess the quality of the body of retrieved evidence and studies risk of bias, inconsistency and imprecision were estimated as low. Conclusion Low dialysate sodium concentration reduces the IDWG in patients on chronic hemodialysis.