Background: Cardiovascular disease (CVD) is the leading cause of morbidity and mortality in patients with chronic kidney disease (CKD). Cardiovascular risk assessment in this population is hampered by the failure of traditional risk factors to fully account for the elevated CVD risk, mainly due to the reverse epidemiology effect, and the presence of risk factors specifically related to uraemia. Hereby, we present the protocol of a prospective study aimed to assess the predictive value of imaging techniques and biomarkers for CVD in patients with CKD. Methods: From November 2009, 2661 asymptomatic adult patients with stages 3-5D CKD will be recruited from nephrology services and dialysis units throughout Spain. Eight-hundred and forty-three participants without CKD (control group) will be also recruited. During the follow-up, CVD events and mortality will be recorded from all CKD patients. One trained itinerant team will carry out a carotid ultrasound to assess intima-media thickness and presence of plaques. A composite atherosclerosis score will be constructed based on carotid ultrasound data and ankle-brachial index. Presence and type of calcifications will be assessed in carotid, femoral and brachial arteries, and in cardiac valves, by ultrasound. Finally, blood samples will be collected from all participants to study biomarkers. Discussion: The NEFRONA study will allow us to examine the usefulness of imaging techniques and biomarkers to assess atherosclerosis development and their predictive value in a Spanish population with CKD.