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. We searched the Cochrane Library, PubMed and Embase databases. Systematic review best practices were followed, and study quality was assessed. 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. Our meta-analysis showed that circulating esRAGE was lower and inversely correlated with IMT in T2D patients. Copyright © 2021 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.