The aim of the present study was transmembrane pressure (TMP) modulation in high-volume mixed hemodiafiltration (HDF) to optimize efficiency and minimize protein loss. The optimal flow/pressure conditions in on-line mixed HDF assisted with a feedback control of TMP were defined in this prospective randomized study in order to obtain maximal efficiency in solute removal while minimizing potential side effects. Two different TMP profiles in mixed HDF were compared in 12 unselected patients who underwent two study periods of 2 weeks each in cross-over randomized sequence: (A) constant TMP at around 300 mmHg and (B) profiled TMP, in which TMP was slowly increased from a low initial value to the maximal value. In both procedures, the mean volume exchange was 10.6+/-1.4 l/h. Mean filtration fraction was 53%. Instantaneous beta2-microglobulin (beta2-m) clearance was higher at the start of the session with profiled TMP (207+/-35 vs 194+/-28 ml/min, P<0.005), whereas no differences were found at the end (135+/-19 vs 132+/-19 ml/min). Profiled TMP resulted in a higher mean beta2-m clearance of the session (97.0+/-15.4 vs 87.8+/-18.3 ml/min, P<0.01), in lower albumin loss in the first 30 min (0.62+/-0.14 vs 0.98+/-0.18 g, P<0.0001), and, in the whole session (3.98+/-1.19 vs 5.24+/-0.77 g, P<0.001), in higher dialyzer ultrafiltration coefficients and lower resistance indexes. This study showed that the TMP feedback modulation in mixed HDF was highly effective in maintaining very high ultrafiltration rates and filtration fractions, and minimized potential side effects as a result of the improved preservation of membrane permeability and more favorable dialyzer pressure regimen.