Abstract Background and Aims Short daily home hemodialysis (HDD) with low dialysate flow rate has been shown in recent years as an attractive alternative for portable dialysis home use. Although the effectiveness of the technique for volume control and elimination of small solutes and middle molecules has been demonstrated, data are scarce for the elimination of protein-bound uremic toxins. The aim of this study was to compare the reduction ratios (RRs) of p-cresol sulfate (pCS) and indoxyl sulfate (IS) in the Physidia HHD system with high-volume online-hemodiafiltration (OL-HDF) treatment. Methods In an open, randomized, cross-over, single-center, controlled study, 40 adult chronic HD patients were treated with a 2.5 h-length HD session with low dialysate flow rate with the Physidia HDD system, and a 4 h-length OL-HDF session in post-dilution mode during two successive weeks. During the sessions, pre-HD and post-HD plasma samples were collected and single and weekly RRs of pC and IS were intraindividually compared for the two dialysis types with linear mixed models. Results Whereas single-session RRs of p-CS and IS were similar in both groups, weekly RRs of both protein-bound uremic toxins were significantly higher with the short-daily HDD Physida system than those obtained with OL-HDF (Table 1). Conclusion The short-daily home hemodialysis using low dialysate flow rate with the Physidia system appears to be a potential technologic step ahead in terms of improved protein-bound uremic toxins removal for dialysis patients, and might contribute to a more adequate dialysis therapy than in-center high-volume online-hemodiafiltration (OL-HDF) treatment.