1. Oedema formation induced by intradermal capsaicin has been studied in rabbit skin. The effect of the anti-inflammatory steroid dexamethasone and also of a range of known inhibitors of oedema formation have been investigated in order to elucidate mechanisms involved in capsaicin-induced oedema formation. 2. Oedema formation, in response to intradermally-injected test agents, was measured by the local extravascular accumulation of intravenously injected 125I-labelled albumin. In separate experiments skin blood flow was assessed by the clearance of intradermally-injected 133xenon. 3. Oedema formation induced by intradermal histamine (3 nmol) and bradykinin (1 nmol), when in the presence of vasodilator doses of calcitonin gene-related peptide (CGRP) (3 pmol) or prostaglandin E1, (PGE1) (10 pmol), was significantly inhibited (P < 0.01) in rabbits pretreated with intravenous dexamethasone (3 mg kg-1, -4 h). In contrast dexamethasone had no effect on capsaicin (3 mumol)-induced oedema formation or, on capsaicin (30-100 nmol)-induced blood flow. 4. Oedema formation observed in response to intradermal capsaicin (3 mumol) was significantly inhibited (P < 0.01) when the selective capsaicin antagonist, ruthenium red (3 nmol) was co-injected. This suggests that the mechanism of capsaicin-induced oedema involves activation of sensory nerves. However, oedema was not inhibited when capsaicin was co-injected with the neurokinin NK1 receptor antagonist, RP67580 (10 nmol), the NK2 antagonist SR48960 (10 nmol) or the CGRP antagonist CGRP8-37 (300 pmol). 5. Oedema formation induced by capsaicin was not inhibited when co-injected with the histamine HI receptor antagonist, mepyramine (3 nmol), the PAF antagonist, WEB 2086 (100 nmol), the bradykinin B2 receptor antagonist, Hoel4O (1 nmol), or the cyclo-oxygenase inhibitor, indomethacin (10 nmol),suggesting that these mediators do not play a major role in the capsaicin-induced response.6. Histological analysis of capsaicin-treated skin sites revealed undamaged, intact microvessels and lack of haemorrhage. Further, co-injection of capsaicin with the hydrogen peroxide remover, catalase(2,200 u), had no effect on oedema formation. This suggests that capsaicin does not induce oedema formation secondary to free radical-induced damage.7. These results indicate that capsaicin-induced oedema in rabbit skin involves activation of sensory nerves. However, the oedema is not inhibited by pretreatment with the anti-inflammatory steroid,dexamethasone. Further the mechanisms which lead to the oedema formation observed after intradermal capsaicin remain unknown.