To test the hypothesis that neurosecretory axon regeneration occurs only in the presence of specific vascular, perivascular, and glial microenvironments, isografts of neural lobe, optic nerve, and autografts of sciatic nerve were transplanted into the hypothalamo-neurohypophysial tract at the lateral retrochiasmatic area;The integrity of the BBB to intravenously administered HRP, the regenerative process of neurosecretory axons, and the functional recovery from the lesion-induced diabetes insipidus were analyzed at 18h, 36h, 10d, 30d, and 80d postsurgery;Neurophysin-positive axons invaded all grafts, as well as perivascular spaces of the adjacent hypothalamus. This neurosecretory axon regeneration was observed only in areas of the grafts or the surrounding hypothalamic tissue where the BBB was breached. Reestablishment of the BBB was paralleled by a decrease in both density and staining intensity of regenerating neurophysin-positive axons. The vast majority of regenerating neurosecretory axons was associated with glial cell types characteristic for each graft type;These observations illustrate that neurosecretory axon regeneration is tributary of the absence of BBB. It is speculated that blood-borne factors, provided during the time when the BBB is breached, initiate and sustain neurosecretory axon regeneration. In addition, products of glial element may enhance or complement the above stimulatory processes.