ABSTRACT: Abstract Objectives Concerns exist that NSBs do not have established benefits, with major dietary guidelines recommending that water and not NSBs replace sugar-sweetened beverages (SSBs). Whether NSBs improve cardiometabolic risk factors similar to water in their intended substitution for SSBs is unclear. To inform the update of the European Association for the Study of Diabetes (EASD) clinical practice guidelines for nutrition therapy, we conducted a systematic review and network meta-analysis to assess the effect of substituting NSBs for SSBs, water for SSBs and NSBs for water on cardiometabolic risk factors in people with and without diabetes. Methods We searched MEDLINE, Embase and the Cochrane Library through March 2019. Randomized controlled trials (RCTs) ? 1 week comparing NSBs, SSBs, and/or water were included. Outcomes were measures of adiposity, glycemic control, lipids, blood pressure, nonalcoholic fatty liver disease and uric acid. Two independent reviewers extracted data and assessed risk of bias. A frequentist network meta-analysis was performed for the substitution of NSBs for SSBs, water for SSBs and NSBs for water. Data were expressed as mean (MD) or standardized mean (SMD) differences with 95% confidence intervals (CI). GRADE assessed certainty of evidence. Results We identified 14 RCTs (n = 1530) substituting NSBs for SSBs (7 trials, N = 483), NSBs for water (7 trials, n = 852) and water for SSBs (2 trials, n = 285) mostly in people at risk for or with diabetes. Substitution of NSBs for SSBs reduced body weight (MD, ?1.11 kg [95% CI, ?1.90 to –0.32]), BMI (?0.32 kg/m2 [?0.58 to –0.07]), body fat (?0.60% [?1.03 to –0.18]), triglycerides (?0.24 mmol/L [?0.45 to ?0.02]), and liver fat (SMD, ?0.44 [95% CI, ?0.69 to –0.19]). Substitution of water for SSBs reduced only uric acid (–0.05 mmol/L [–0.08 to ?0.01]). There was no effect of substituting NSBs for water on any outcome except HbA1c (0.21% [0.02 to 0.40]). The certainty of the evidence ranged from low to high. Conclusions The intended substitution of NSBs for SSBs improves cardiometabolic risk factors, showing similar benefits to water. The available evidence supports the use of NSBs as an alternative replacement strategy for SSBs. There is a need for more high-quality RCTs. (ClinicalTrials.gov identifier, NCT02879500) Funding Sources Diabetes and Nutrition Study Group of the EASD, CIHR, Diabetes Canada.