Hemofiltration (HF) is used extensively for continuous renal replacement therapy, but long-term treatment is limited by thrombosis leading to fiber clogging. Maximum filter life is typically less than 20 h. We have achieved for the first time continuous and consistent hemofiltration for more than 100 h using outside-in hemofiltration with the blood flow into the inter-fiber space (IFS). Although thrombi do deposit in the IFS, they have minimal affect on the blood flow and filtrate flux due to the three-dimensional system of interconnected hydrodynamic flow channels in the IFS. Microscopic examination of sections of the fiber bundle showed that deposited thrombi have dimensions about the size of the gaps between the hollow fibers and remain isolated from each other. A simple mathematical model is developed to describe the effect of thrombus deposition on the fluid flow that accounts for the enhanced performance arising from the interconnected flow. The hydrodynamic advantage of outside-in HF decreases at low anticoagulant concentration due to the instability in the blood and the very high volume fraction of thrombi that deposit in the entrance zone of the filter. These results clearly demonstrate the significant potential advantages of using outside-in hemofiltration for long-term renal replacement therapy. (C) 2014 Elsevier B.V. All rights reserved.