Background: Adiponectin and complement factor D are harmful large middle molecules that accumulate in patients with end stage renal disease. High-dose hemodiafiltration (HDF) has recently shown a clear survival benefit. Objective: In this study we aimed to compare the removal of adiponectin and complement factor D in patients on HDF versus high flux hemodialysis (HD) using two different high flux dialysers. Patients and Method: This is a cross over clinical trial. Twenty hemodialysis patients were enrolled. Dialyser and treatment efficacies were examined during a mid-week session with the following treatments HD FX 80, HD H4, HDF FX80, HDF H4. Treatment efficacy was assessed by calculating the reduction ratio (RR) of adiponectin and complement factor D before and after each session. Results: Twenty dialysis patients aged 50.5 ± 10.4 years. During HDF urea reduction ratio (URR) was 70.4 ± 6.8 compared to 65.1 ± 7 during HD. Adiponectin RR using HDF FX80 was 48.1 ± 9.3 compared to 32.2± 9 with HD FX80, p <0. 001. Adiponectin RR using HDF H4 was 46.7 ±12.2 compared to 31.1± 9.4 with HD H4, p < 0. 001. Complement factor D RR using HDF FX80 was 48.1 ± 13 compared to 29.8±9.6 with HD FX80, p < 0.001. Complement factor D RR using HDF H4 was 46.7±12.2 compared to 26.6 ± 7.5 using HD H4, p < 0.001.  Conclusion: High- dose HDF offered better removal of adiponectin and complement factor D compared to high flux HD. No difference was observed between the two high flux dialysers used.