The rate of entry of albumin into the endoneurial space and its content within that compartment during development were investigated by measuring the permeability coefficient-surface area product to 125I-albumin (PSA) of the blood-nerve interface (BNI), endoneurial residual plasma volume (Vp), blood-nerve interface index to albumin, and endoneurial water content in sciatic nerves of rats ranging in age from 1 to 24 weeks. There was a 30-fold reduction in PSA and a 4-fold decrease in Vp from 2 to 24 weeks, indicating that the endoneurial capillaries and perineurium become less permeable during development. On the other hand, the Alb-BNI index was relatively small at 1 week, increased to a peak value around 6-8 weeks, and then decreased to adult values by 13 weeks. The smaller Alb-BNI index in the neonatal period is consistent with endoneurial albumin being cleared across a permeable perineurium by epineurial lymphatics. Subsequently, as the perineurium becomes less permeable, endoneurial albumin content increases. It then decreases as the endoneurial capillary permeability also decreases. Additionally, metabolic clearance of albumin, especially during the first 2-3 weeks, by axons and glia to meet the nutritive requirements of rapid axonal growth and myelination could be partly responsible for a lower Alb-BNI index. It is suggested that in the developing nerve, the combination of epineurial lymphatics and a relatively permeable perineurium, together with axonal and glial uptake and protein catabolism aid in the clearance of plasma-derived osmolytes from the endoneurial space, and thus prevent the elevation of endoneurial hydrostatic pressure and onset of oedema that would have been seen in an adult nerve with a comparably permeable BNI.