1. The temporal and quantitative effects of inflammatory mediators on plasma extravasation in the rat knee were investigated by use of a perfusion technique. 2. Intra-articular perfusion of substance P (SP), bradykinin or histamine over a 5 min test period produced rapid-onset and prolonged plasma extravasation in a dose-dependent fashion. The rank order of potency was bradykinin greater than SP greater than histamine. 3. Calcitonin gene-related peptide (CGRP) did not induce plasma extravasation but enhanced substance P-induced plasma extravasation in a dose-dependent fashion. A 5 min co-perfusion of the two agents produced short-term enhancement lasting 10 min while continuous co-perfusion produced enhancement for the duration of the perfusion. 4. A 5 min perfusion of CGRP enhanced plasma extravasation when co-perfused with bradykinin but not histamine. However, when CGRP and histamine were continuously co-perfused over a 20 min test period, an enhanced response was apparent. 5. The results indicate that intra-articular perfusion of CGRP enhances synovial plasma extravasation induced by agents that increase vascular permeability, but suggest that the response is not uniform and is critically dependent on the duration of perfusion within the joint.