A method for perfusion of cat paws with constant flow and temperature is described. This technique has been used to study the relationship between the efflux of histamine and slow reacting substance (SRS) from cat paws perfused with compound 48/80. The threshold dose of compound 48/80 was 0.001–0.01 μg/ml for both histamine and SRS releasing effects. No correlation between the yields of histamine and SRS was noted. On repeated administration of compound 48/80 the histamine releasing effect declined and the output of SRS was cor respondingly reduced. The release of histamine and the formation of SRS were inhibited by ninhydrin, N-ethylmaleimide and potassium cyanide indicating that both processes are dependent on energy-requiring enzymatic reactions. Apart from their antagonism of the histamine releasing effect of compound 48/80, ninhydrin and N-ethylmaleimide released histamine per se. No SRS was detected in the effluents from paws perfused with these agents alone. The yields of both histamine and SRS were higher at 22o C than at 37oC. Regardless of temperature the efflux of histamine consistently preceded that of SRS. A temperature dependent inactivation of SRS by cat serum was demonstrated. The results suggest that the initial reaction(s) activated by compound 48/80 is common for the release of histamine and the formation of SRS in the cat paw but that these processes then proceed independently.