Background and Aims: Whether proton pump inhibitors (PPI) can improve glycemic control is unclear. Also, incident diabetes from PPI use has not been elucidated. We conducted a meta-analysis and systematic review to determine the impact of PPI on glycemic control in individuals with diabetes and the risk of diabetes in those without diabetes. Methods: PubMed, Embase, Scopus, and ClinicalTrials.gov were searched from inception to November 21, 2020. Studies reporting a change of glycemic indices, including glycosylated hemoglobin (HbA1c) or fasting blood glucose (FBG), in individuals with diabetes taking add-on PPI compared to standard therapy were included. Also, studies evaluating risk of incident diabetes in individuals taking PPI were assessed. We performed dual independent review, data extraction, and quality assessment. Weighted mean differences or relative risks were imputed using random-effects models. Results: Seven studies (n = 342) for glycemic control, and five studies (n = 244,439) for risk of incident diabetes were included. Compared to standard therapy, add-on PPI was associated with a significant decrease in HbA1c (WMD = −0.36 %; 95% CI: −0.68 to −0.05; p = 0.025), and FBG (WMD = −10.0 mg/dL; 95% CI: −19.4 to −0.6; p = 0.037). However, PPI use was not significantly associated with the risk of incident diabetes (pooled RR = 1.10; 95% CI: 0.89 to 1.34; p = 0.385). Conclusions: PPI along with standard care improved glycemic indices in individuals with diabetes but did not alter the risk of incident diabetes. The effects of PPI on glycemic control should be considered when treating upper gastrointestinal symptoms in patients with diabetes. Disclosure C. Peng: None. K. Bukhari: None. H. Huang: None. Y. Tu: None. G. Lee: None. H. Chang: None. Y. Huang: None. Y. Fu: None. K. M. Munir: None.