Hypoalbuminemia predicts mortality in hemodialysis patients with end-stage renal disease (ESRD) and is assumed to result from malnutrition. We report here that plasma albumin levels are reduced significantly in both hemodialysis and peritoneal dialysis (PD) patients compared to normal subjects. Among hemodialysis patients with normal albumin levels (the upper quartile of albumin distribution), albumin synthesis rates, fractional catabolic rates, and distribution between the vascular and extravascular pool are normal, suggesting that ESRD per se does not derange albumin metabolism. Albumin synthesis is reduced in hemodialysis patients who are hypoalbuminemic, but the fractional albumin catabolic rate decreases normally, and albumin distribution between the vascular and extravascular space remains normal, suggesting that hypoalbuminemia results primarily from decreased synthesis. Using multiple linear regression analysis, the strongest correlates to plasma albumin concentration in 115 hemodialysis patients were the plasma level of the acute-phase C-reactive protein (CRP) and the normalized protein catabolic rate (PCRn). These two independent predictors of plasma albumin concentrations are markers of inflammation and of protein intake, respectively. CRP levels correlate more strongly with albumin concentration than does low PCRn. Activity of the acute-phase response is an important predictor of low plasma albumin concentration in hemodialysis patients independently of nutritional factors. External loss of albumin in the dialysate is an additional factor that contributes significantly to hypoalbuminemia in PD patients.