In this study, the contribution of the nose-CSF pathway in the uptake of hydrocortisone into the cerebrospinal fluid (CSF) was determined by comparing the intranasal and intravenous routes of administration. A vascular access port was used as the intravenous delivery device. The effect of different nasal delivery volumes on the uptake of hydrocortisone into plasma and CSF was also investigated. Male Wistar rats were given hydrocortisone (280 μg/rat) intranasally in volumes of 20, 40 and 60 μl, by intravenous bolus injection (280 μg/rat) to determine the infusion rate and to achieve the same C max as obtained after nasal delivery, and by intravenous infusion (0.14 mg/ml, 68 μl/min for 15 min). Increasing the nasal delivery volume from 20 to 60 μl did not have any further effect on the absorption of hydrocortisone in plasma or the uptake in CSF. The C observed after intravenous infusion was higher than that obtained after intranasal delivery, but these did not differ significantly. The amount of hydrocortisone in CSF was of the order of 3-4% of that found in plasma after both routes of administration. There is thus no indication for the nose-CSF transport of the lipophilic steroid hormone hydrocortisone after nasal administration.