Background: Arteriovenous fistula dysfunction is a widely disputed subject in the scientific literature on end-stage kidney disease (ESKD). The main cause of mortality and morbidity in these patients is the non-maturation or dysfunction of the arteriovenous fistula. Despite the many complications, the native arteriovenous fistula remains the gold standard in the treatment of these patients requiring renal replacement. This study aims to discuss the predictive role of some systemic inflammatory biomarkers (NLR, PLR, SII, IL-6), intimal hyperplasia, and neoangiogenesis (characterized by intimal-media CD31-positive relative surface) in arteriovenous fistula maturation failure. Methods: The present study was designed as an observational, analytical, and prospective study which included patients diagnosed with ESKD with indications of radio-cephalic arteriovenous fistula (RCAVF). Demographic data, comorbidities, preoperative laboratory data and histological/digital morphometry analysis results were processed. The patients included were divided into two groups based on their AVF maturation status at 8 weeks: “Maturation” (Group 1) and “Failed Maturation” (Group 2). Results: There was no difference in the demographic data. In terms of comorbidities, the second group had a greater incidence of heart failure (p= 0.03), diabetes (p= 0.04), peripheral artery disease (p= 0.002), and obesity (p= 0.01). Additionally, regarding the laboratory findings, these patients had higher levels of serum uric acid (p= 0.0005), phosphates (p< 0.0001), and creatinine (p= 0.02), as well as lower levels of total calcium (p= 0.0002), monocytes (p= 0.008), and lymphocytes (p< 0.0001). Moreover, all inflammatory markers (p= 0.001;p< 0.0001;p= 0.006, andp= 0.03) and Ca-P product (p< 0.0001) had higher baseline values in Group 2. Upon immunohistochemical analysis, regarding the density of neoformed vessels, there was a higher incidence of CD31-positive surfaces (p= 0.006) and CD31-positive relative surfaces (p= 0.001); the NLR (r = 0.323;p= 0.03), PLR (r = 0.381;p= 0.04), SII (r = 0.376;p= 0.03), and IL-6 (r = 0.611;p< 0.001) are all significantly correlated with vascular density, as evidenced by CD31. Conclusions: Heart failure, peripheral artery disease, obesity, and diabetes, as well as the systemic inflammatory markers (NLR, PLR, SII, IL-6), intimal hyperplasia, and CD31-positive relative surfaces are predictors of arteriovenous fistula maturation failures.