Elimination of uremic solutes with molecular weights up to 60 kD, without significant loss of albumin is an important therapeutic goal to optimize outcomes in chronic hemodialysis patients. To characterize a newly developed polysulfone dialyzer (APS-650) a comparative analysis was performed with a highly advanced polysulfone dialyzer (F-60S) including 22 stable chronic hemodialysis patients. Diffusive clearances were determined, and albumin loss was calculated. The elimination profile of uremic solutes up to 32.0 kD was assessed in vivo by sieving coefficients, clearances, and reduction ratios of β<sub>2</sub>-microglobulin (11.8 kD), myoglobin (17.2 kD), prolactin (23.0 kD), and α<sub>1</sub>-microglobulin (32.0 kD). Hemocompatibility was tested in serial measurements of total white blood cell count, platelet count, C3a, and neutrophil elastase. No significant albumin loss was detected. Significantly higher sieving coefficients, clearances, and reduction ratios for proteins with molecular weight up to 32.0 kD were demonstrated with the newly developed polysulfone membrane. Both polysulfone membranes were equal concerning hemocompatibility parameters. The APS-650 dialyzer allowed optimized hemodialysis treatment with respect to clearance of medium-sized uraemic solutes by high-flux dialysis.