This study describes the use of microdialysis technique for continuous measurement of plasma protein extravasation (PPE) in rat and mouse skin with application of the drugs either intravenously or via the microdialysis fiber. Hollow plasmapheresis fibers (3 cm length, 0.4 mm diameter and cut off 3000kDa) were placed subcutaneously on the back of anaesthetized mice and rats. Intravenous injection of dextran (macrodex 60 mg/ml) increased PPE by 355 % from baseline within 30 min in rats with ligated kidneys (n=6, p<0.05), but not in animals with intact kidneys. Phalloidin (500 µg/kg i.v. 40 min prior to dextran) (n=6, p<0.05) did not change the response to phalloidin in either group. The animals receiving prostaglandin E₁ (PGE₁), Compound 48/80 (mice), paclitaxel, docetaxel and cremophor-E1® via the microdialysis fiber were also provided with a control fiber receiving vehicle. Both rats and mice had constant PPE in the control fiber and there was no change in PPE in the NaCl treated groups, (rats: n=4 and mice: n=6). Application via the fibre of PGE1 (20 µg/ml), compound 48/80 (mice) (4 mg/ml) and docetaxel (0.5mg/ml) increased PPE compared to baseline within 60 min by 139% (n=6, p<0.05), 273% (n=6, p<0.05) and 325 % (n=5, p<0.05), respectively. Phalloidin alone did not increase PPE (n=5, p<0.05). Pretreatment with phalloidin did not inhibit the increase after PGE1 or C48/80, but inhibited the increase seen after docetaxel (n=6). Paclitaxel (0.6 mg/ml, n=5) as well as vehicle (cremophore) (n=5) gave no increase in PPE. The results demonstrate that microdialysis can be used to continuously measure changes in PPE following inflammatory challenges in skin of rats and mice.