The aim of this systematic review is to investigate the effects of the use of a medium cut-off membrane (MCO) and dietary fiber on the concentration of protein-bound uremic toxins (PBUTs) and inflammatory markers in hemodialysis (HD) patients. Of 11,397 papers originally found, eight met the criteria of randomized controlled trial design. No study examined the effects of MCO membranes on PBUTs. Three studies examined the reduction in inflammatory markers with MCO membranes compared to high-flux HD membranes and showed no significant differences. Five studies of dietary fiber supplementation showed an inconclusive positive effect on PBUT levels and a significant positive effect on the reduction in inflammatory markers (interleukin-6 reduction: standardized difference in means −1.18; 95% confidence interval −1.45 to −0.9 for dietary fiber supplementation vs. control; p < 0.001). To date, no study has combined the use of an MCO membrane and fiber supplementation to reduce PBUT levels and inflammation with online hemodiafiltration as a comparator. A rationale and protocol for an interventional trial using a combination of MCO membrane dialysis and fiber supplementation to lower inflammatory markers and PBUT concentrations are presented.