Nutritional status in hemodialysis patients is a strong predictor of morbidity and mortality. To isolate the impact of dialyzer flux on nutrition in hemodialysis patients, we compared the nutritional effect of high-flux dialysis with that low-flux dialysis, using a biocompatible membrane for both. Sixty-five patients were monitored for 8 months after changing to high-flux dialysis with a F80 polysulfone dialyzer following a 6-month baseline period of low-flux dialysis with a F8 polysulfone dialyzer. The Kt/V and normalized protein catabolic rate (nPCR) were the same on both the F8 and F80 dialyzers. The regression of nPCR versus Kt/V was also nearly identical. Despite the unchanged protein intake, the serum albumin (3.86 to 4.04 g/dL; P < 0.01) and serum creatinine (10.3+/-0.2 mg/dL to 11.2+/-0.3 mg/dL; P < 0.05) significantly increased during 8 months of high-flux dialysis. Therefore, we conclude that the increased removal of middle molecules by high-flux dialysis has no apparent effect on appetite as measured by nPCR, but it has a beneficial effect on serum albumin and serum creatinine, suggesting a role for middle molecules in the control of albumin and protein synthesis in the body.