Hyperphosphatemia contributes to increased cardiovascular mortality through vascular calcification (VC) in patients with chronic kidney disease (CKD). Malnutrition and inflammation are also closely linked to increased risk of cardiovascular death in CKD. However, the effects of Pi overload on inflammation and malnutrition remain to be elucidated. The aim of the present study was to investigate the effects of dietary phosphate loading on the interaction among inflammation, malnutrition and VC in CKD. We used control rats fed normal diets and adenine-induced CKD rats fed diets with different phosphate concentrations ranging from 0.3% to 1.2% for 8 weeks. CKD rats showed dietary phosphate concentration-dependent increases in serum and tissue levels of tumor necrosis factor-α, and urinary and tissue levels of oxidative stress markers, and developed malnutrition (decrease in body weight, serum albumin and urinary creatinine excretion), VC and premature death without affecting kidney function. Treatment with 6% lanthanum carbonate blunted almost all changes induced by phosphate overload. Regression analysis showed that serum phosphate levels closely correlated with the extent of inflammation, malnutrition and VC. Also, in cultured human vascular smooth muscle cells, high-phosphate medium directly increased the expression of tumor necrosis factor-α in advance of the increase in osteochondrogenic markers. Our data suggest that dietary phosphate overload induces systemic inflammation and malnutrition, accompanied by VC and premature death in CKD, and inhibition of phosphate loading through dietary or pharmacological interventions, or anti-inflammatory therapy may be a promising treatment for the prevention of malnutrition-inflammation-atherosclerosis syndrome.