Hypoalbuminemia predicts mortality in hemodialysis patients with end-stage renal disease and is assumed to result from malnutrition. To investigate a possible alternative cause, we evaluated the relationships between serum albumin (Salb) and serum levels of two positive acute-phase proteins: C-reactive protein (CRP) and serum amyloid A (SAA). We also examined the relationship between Salb and dialysis dose delivered (Kt/V) and normalized protein catabolic rate (PCRn) measured during 3 consecutive months in a group of 115 patients. Serum albumin was measured monthly for 5 months. SAA levels were not increased in the majority of patients, despite its low molecular weight (8 kd), and predialysis concentrations were independent of residual renal function, compatible with a nonrenal site of metabolism. Both CRP and SAA levels correlated negatively with Salb both by linear regression and by multiple regression analysis (P < 0.001). CRP correlated with fibrinogen (P < 0.005). Salb also correlated positively with PCRn (P = 0.001), but not with Kt/V. The Kt/V did not correlate with PCRn. While CRP and SAA correlated with one another, neither variable correlated with PCRn. When either SAA or CRP was high, Salb was low regardless of PCRn. Thus, there are two separate independent factors predicting Salb--markers of inflammation and protein intake--but high concentrations of acute-phase proteins have a greater impact on Salb than does low PCRn. Activity of the acute-phase response is an important predictor of low Salb in hemodialysis patients independently of nutritional factors.