Although hemodiafiltration (HDF) offers the advantage of increased convective clearance for middle molecules, there is still controversy as to whether reinfusion should occur pre- or post-filter. Mid-dilution hemodiafiltration (MD HDF) is a new HDF technique that uses a special dialyzer, MD190, which allows both pre- and post-reinfusion. While externally the dialyzer looks similar to conventional hemodialyzers, the internal fibers are divided into two bundles by a special annular header that first lets the blood pass through the peripheral bundle in post-dilution, mix with the reinfusion fluid at the opposite end of the dialyzer and then proceed (after pre-dilution) to the dialyzer blood exit. The dialyzer is able to support substantially higher reinfusion rates (10-12 l/h). We have compared the removal characteristics of several small solutes and larger middle-molecular-weight toxins by examining instantaneous clearance at 45 min, the dialysis reduction ratio and total mass removal (by spilling) in a three-center prospective cross-over study. Twenty patients were randomized to a treatment sequence of one-week high-flux bicarbonate hemodialysis (HD) followed by MD HDF, or vice versa. The parameters evaluated included urea, creatinine, beta2-microglobulin, angiogenin, leptin, retinol-binding protein, and the effects on sodium, potassium, bicarbonate and calcium. Blood flow rates ranged between 300-450 ml/min (mean 359 +/- 44 HD, 367 +/- 35 MD HDF). The mean reinfusion for MD HDF was 166 +/-17 ml/min. MD HDF had a significantly better instantaneous clearance for urea (328 +/- 28 vs 277 +/- 40); creatinine (292 +/- 32 vs. 212 +/- 66); phosphate (324 +/- 38 vs. 242 +/- 63); beta2-microglobulin (249 +/- 27 vs. 100 +/- 24); angiogenin (173 +/- 27 vs. 28 +/- 32); and leptin (202 +/- 29 vs. 63 +/- 43). Treatments were well tolerated with no adverse reactions occurring during any of the treatments. The MD HDF filter's unique configuration is designed to deliver high-efficiency HDF with a significant improvement in small and middle molecule removal. MD HDF supports substantially higher ultrafiltration rates, and as such, results in a higher removal of middle-molecular-weight toxins.