To evaluate long-term effects of different hemodialysis (HD) membranes and techniques on nutritional status, morbidity, and mortality in HD patients, we prospectively studied 138 stable HD patients (59 females, 79 males, mean age 53 +/- 13 yrs) on maintenance HD from at least 1 yr with bicarbonate (BD) and cellulose acetate (AC). Patients were randomly assigned to one of four groups: comparable for age, sex, underlying nephropathy, time on dialysis, comorbidity, and followed-up for 5 yrs. Group A (n=38) BD/AC; group B (n=30) BD/low-flux polysulfone (PS); group C (n=30) BD/middle-flux PS or PA; group D (n=20) hemodiafiltration (HDF)/high-flux polysulfone (PS-HDF); group E (n=20) acetate free biofiltration (AFB) with PAN. Nutritional status was evaluated by anthropometric index, visceral protein compartment index, immunological index and bioelectrical impedance analysis. In all patients, we evaluated yearly plasma values of Beta2-microglobulin and of C-reactive protein (CRP) before and after dialysis. A significant and sustained improvement in nutritional status and a striking reduction in CRP and in pre- and post-dialysis beta2-microglobulin levels was observed in groups C, D and E. Morbidity (calculated from the number of clinical complications/patient/yr and from the number of hospital admissions/patient/yr) and mortality were significantly higher in groups A and B (mortality: group A=24%, group B=23%, group C=10%, group D=5%, and group E=5%; p<0.001). The results of our study indicate that the use of middle and high-flux biocompatible membranes is associated with a remarkable and sustained amelioration in nutritional status and with a significant improvement in the prognosis of HD patients, explained by the notable reduction in beta2-microglobulin and in the systemic inflammatory response.