Significance Statement Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. In this randomized, controlled trial, treatment with sodium bicarbonate (NaHCO₃) did not improve vascular endothelial function or reduce arterial stiffness in participants with CKD stage 3b–4 with normal serum bicarbonate levels. In addition, NaHCO₃ treatment did not reduce left ventricular mass index. NaHCO₃ did increase plasma bicarbonate levels and urinary citrate excretion and reduce urinary ammonium excretion, indicating that the intervention was indeed effective. NaHCO₃ therapy was safe with no significant changes in BP, weight, or edema. These results do not support the use of NaHCO₃ for vascular dysfunction in participants with CKD. Background Lower serum bicarbonate levels, even within the normal range, are strongly linked to risks of cardiovascular disease in CKD, possibly by modifying vascular function. Prospective interventional trials with sodium bicarbonate (NaHCO₃) are lacking. Methods We conducted a randomized, double-blind, placebo-controlled trial examining the effect of NaHCO₃ on vascular function in 109 patients with CKD stage 3b–4 (eGFR 15–44 ml/min per 1.73 m²) with normal serum bicarbonate levels (22–27 mEq/L). Participants were randomized 1:1 to NaHCO₃ or placebo at a dose of 0.5 mEq/lean body weight-kg per day for 12 months. The coprimary end points were change in brachial artery flow-mediated dilation (FMD) and change in aortic pulse wave velocity over 12 months. Results Ninety patients completed this study. After 12 months, plasma bicarbonate levels increased significantly in the NaHCO₃ group compared with placebo (mean [SD] difference between groups 1.35±2.1, P = 0.003). NaHCO₃ treatment did not result in a significant improvement in aortic pulse wave velocity from baseline. NaHCO₃ did result in a significant increase in flow-mediated dilation after 1 month; however, this effect disappeared at 6 and 12 months. NaHCO₃ resulted in a significant increase in 24-hour urine citrate and pH and a significant decrease in 24-hour urine ammonia. There was no significant change in left ventricular mass index, ejection fraction, or eGFR with NaHCO₃. NaHCO₃ treatment was safe and well-tolerated with no significant changes in BP, antihypertensive medication, weight, plasma calcium, or potassium levels. Conclusion Our results do not support the use of NaHCO₃ for vascular dysfunction in participants with CKD and normal serum bicarbonate levels.