Intraplantar injection of canatoxin (CNTX) induced a dose-dependent rat hind-paw edema which was distinguished by two phases. In the first phase, observed between 0 and 2 hr after CNTX injection, there was an increase in paw volume, with no apparent involvement of inflammatory phagocytic cells. The second phase, beginning at about the 3rd hr, was characterized by an intense cellular infiltration at the site of administration which was coincident with a further increase in paw swelling. The edema was maximum at 6 hr after injection and disappeared within 48 hr at doses of 50-100 micrograms, while at doses of 200-300 micrograms edema was present in excess of 48 hr. The pharmacological studies suggested that CNTX-induced edema is a multi-mediated phenomenon. Histamine, serotonin, PAF and prostaglandins are likely involved in the first phase. Lipoxygenase metabolites, probably leukotrienes, seem to play a major role in the second phase, and may account for the development of cellular infiltration in the inflammatory site.