Cardiovascular disease (CVD) is the most prominent cause of morbidity and mortality among patients with chronic kidney disease (CKD), and end stage kidney disease (ESKD). Unfortunately at the present time, we do not have an effective treatment to reduce the high CVD mortality in these populations. Accelerated atherosclerosis, inflammation, and vascular stiffness are prominent factors contributing to CVD in CKD. Interventions that can effectively counter these factors may provide significant benefits for the management of CVD in CKD. Hydroxychloroquine (HCQ) is an inexpensive and safe anti-inflammatory drug that has been in clinical use for over 4 decades even in patients with CKD and ESKD. In recent times, multiple in vitro, in vivo, and human cohort based data have shown that HCQ benefits multiple parameters of CVD, including inflammation, endothelial function, metabolic syndrome, insulin sensitivity and atherosclerosis. Recently we through our animal validated that HCQ indeed has significant anti-atherosclerosis and vasculoprotective effects in CKD milieu. We further conducted a small, human, feasibility study that shows a potential for HCQ on parameters relevant to CVD in CKD. The next step requires evaluation of HCQ's role for the treatment of CVD in CKD. However, in the absence of a universally agreed-on surrogate for CVD, a proof-of-concept clinical study needed to validate the anti- atherosclerosis and vasculoprotective potential of HCQ in CKD. We propose such a study that will enroll 90 albuminuric, stage 3b CKD subjects in a randomized controlled trial (RCT) with 1:1 allocation (HCQ : placebo), stratified by their diabetes status, and treat for a duration of 18 months. We will examine the effects of HCQ on structural, functional, and biochemical measures of atherosclerosis and CVD. Specific Aim (SA) 1 will evaluate the ability of HCQ, compared to placebo, to slow the progression, or reverse atherosclerosis. We will evaluate the progression of carotid atherosclerosis with a non-contrast MRI performed at baseline and after 9 and 18 months of treatment with HCQ or placebo. The primary outcome measure will be change in total carotid plaque volume (TPV). Secondary outcome measures will be changes over time in total plaque surface area, maximal stenosis, and the type (fibrous, stable, or unstable), and stability of plaques. Specific Aim 2: will evaluate the extent to which HCQ can affect inflammation (SA2a), and vascular stiffness (SA2b) in CKD. We will examine the effects of HCQ and placebo at baseline, and at 6, 9, 12, and 18 months on the secondary outcome measures of high-sensitivity C-reactive protein (SA2a) and aortic pulse wave velocity (SA2b). Though the sample size and power calculations have been designed for the primary outcome (SA1), we will have adequate power to evaluate meaningful impacts of HCQ on the secondary outcomes in SA2. Specific Aim 3 will examine the effect of HCQ and placebo on the trends of hard cardiac and renal outcomes and drug safety. While not powered to detect the differences in the rates of these clinical events, trends in outcomes, drug safety, and tolerability are mandatory and will assist in the planning of the future, definitive RCT. If the results of this trial are positive with a favorable AE profile, it will provide critical preliminary data to justify and plan a definitive, multicenter RCT to examine the effects of HCQ on hard outcomes of CVD in CKD. Additionally, this study may provide insights into the importance of select inflammatory and vascular factors in CVD with wider future implications for those with CKD and perhaps the general population.