Background: The soluble receptor for advanced glycation end product (sRAGE) and endogenous secretory RAGE (esRAGE) are novel biomarkers that are associated with vascular disease. We carried out a systematic review to provide a more complete picture of sRAGE, esRAGE, carotid atherosclerosis and cardiovascular disease (CVD) in patients with diabetes. Methods: We searched the Cochrane Library, PubMed and Embase databases. Systematic review best practices were followed, and study quality was assessed. Results: Ultimately, 11 studies met all the inclusion criteria. Meta-analysis indicated that esRAGE was not significantly lower in patients with type 1 diabetes (T1D) (standardized mean difference [SMD], −0.76; 95% confidence interval [CI], −1.57 to 0.05; I2=90%; p=0.002), whereas it was significantly lower in patients with type 2 diabetes (T2D) (SMD, −1.08; 95% CI, −1.53 to −0.62; I2=80%; p=0.006). Meta-analysis suggested that sRAGE levels were not significantly lower or higher in T1D (SMD, 0.06; 95% CI, −0.14 to 0.26; I2=38%; p=0.20) or T2D (SMD, 0.00; 95% CI, −0.26 to 0.26; I2=0.00%; p=1.00) patients. The level of esRAGE was inversely correlated with carotid intima-media thickness (IMT) in T2D patients, whereas there was a contrasting relationship between sRAGE and carotid IMT in T1D patients. Higher sRAGE was associated with cardiovascular events. Conclusion: Our meta-analysis showed that circulating esRAGE was lower and inversely correlated with IMT in T2D patients. © 2021 Canadian Diabetes Association