Background and Aim. Chronic kidney disease (CKD) and its final stage: end-stage renal disease (ESRD), are common clinical conditions. Endocan is a human endothelial cell-specific molecule produced by endothelial cells. Its production is related to activation of endothelium and angiogenesis. In this study, we assessed the relation between serum endocan levels and subclinical atherosclerosis (SCA) in CKD and hemodialysis (HD) patients. Subjects and Methods. The present case control study enrolled 30 patients on regular HD for at least 6 months, 30 patients with CKD, and 30 age and sex-matched healthy controls. All participants were subjected to careful history taking and thorough clinical examination. Laboratory investigations included complete blood count, kidney functions, and serum cholesterol, triglycerides, calcium, phosphorus, albumin, PTH, hsCRP, and endocan levels. Results. HD and CKD groups had significantly higher endocan levels when compared with control group (median (IQR): 519.0 (202.3–742.0) versus 409.0 (245.3–505.3) and 273.0 (168.0–395.5) ng/L, respectively). Also, HD patients had significantly higher endocan levels when compared with CKD levels. HD patients had significantly higher carotid intima-media thickness (CIMT) when compared with CKD patients (median (IQR): 0.80 (0.80–0.90) versus 0.75 (0.73–0.75) mm, p < 0.001 ). HD patients had significantly higher frequency of SCA when compared with CKD patients (46.7% versus 13.3%, p = 0.005 ). Patients with SCA had significantly higher hsCRP (median (IQR): 36.5 (26.8–43.5) versus 24.0 (15.8–29.0) mg/dl) and endocan levels (697.0 (528.3–974.8) versus 222.5 (158.8–565.8) ng/L) when compared with patients without SCA. ROC curve analysis of endocan for identification of SCA in HD patients showed that at a cutoff of 380.5 ng/L, endocan has an AUC of 0.862 with a sensitivity and specificity of 92.9% and 68.7%, respectively. Conclusions. Serum endocan levels are related to SCA in HD patients. In addition, it is associated with the hyperinflammatory state in those patients.