Study Objective: The objective of the study is to compare the anti-factor Xa (AXa) level in the blood, after arterial and venous line administration of equivalent doses of enoxaparin for prevention of thrombosis in the extracorporeal blood circuit. Design: The design of the study is a dual centre, prospective, open-labelled randomized crossover, 7 weeks trial. Setting: The setting of the study is on a patient on long-term haemodialysis (HD) or haemodiafiltration (HDF) using high-flux membrane. Participant: There were eight patients on HD and eight on HDF. Intervention: Participants were randomly assigned to receive enoxaparin either through the arterial line or venous line of extracorporeal blood circuit for an initial study interval of 2 weeks, followed by 2 weeks of alternate route administration. During the run-in period of 1 week and the follow-up period of 2 weeks, enoxaparin was administered through the arterial line. Outcomes: The primary outcome measure was to compare AXa blood level 4 h after enoxaparin administration. The secondary outcome measures were manual compression time to stop bleeding from arteriovenous fistula, extracorporeal circuit clotting and systemic bleeding episodes. Results: The mean AXa blood level, 4 h after venous circuit administration (0.58 ± 0.21 (HD), 0.82 ± 0.29 (HDF)) of enoxaparin, was significantly greater than that after arterial administration of enoxaparin (0.39 ± 0.25 (HD), 0.39 ± 0.14 (HDF) U/mL), (P< 0.001). Conclusion: In patients on HD or HDF, venous line administration of enoxaparin achieves greater 4 h blood AXa level compared with arterial line administration of equivalent dose. Based on this, we suggest a 25% or 50% reduction in the dose of venous line enoxaparin, compared with the dose administered through arterial line in patients receiving either HD or HDF, respectively.