The pleiotropic cytokine osteopontin (OPN) is found to be involved in the pathogenesis of both kidney and cardiovascular disease (CVD). We evaluated the relationship between OPN, other cardiovascular risk factors and carotid intima-media thickness (CIMT) in chronic kidney disease (CKD) (predialysis) patients. This is a 2-year cross-sectional prospective study involving 75 patients with CKD from stage 1 to stage 5 attending the nephrology outpatient department and 25 healthy controls. Routine biochemical parameters were analyzed on clinical chemistry Autoanalyzer Beckman Coulter DXC 600 Synchron, USA. OPN was estimated by ELISA method. Carotid intima-media wall thickness was estimated by Doppler of carotid vessels. Serum OPN and other nontraditional cardiovascular risk factors such as CIMT, lipoprotein (a) Lp(a), fibrinogen, and homocysteine were significantly increased in patients of CKD compared to controls. OPN, Lp(a), fibrinogen, CIMT, parathyroid hormone, and homocysteine progressively increased from early stages of CKD and increased further with progression of the disease, but nitric oxide (NO) level progressively decreased with progression of CKD. OPN showed a positive correlation with CIMT, Lp(a), fibrinogen, and homocysteine and negative correlation with estimated glomerular filtration rate and NO. There was a close direct association between circulating levels of OPN and the presence of atherosclerotic plaques in carotid arteries of patients with CKD. Osteopontin and nontraditional CVD risk factors are altered in early stages of CKD and might predict adverse outcomes in these patients.