Isolated rat peritoneal mast cells were exposed to compound 48/80 in A isotonic salt solution and in B isotonic sucrose solution. In both cases degranulation and histamine release occurred. In A all the released histamine appeared dissolved in the suspension medium, the discharged granules having lost their histamine. In B the discharged granules were show to retain histamine. These granules released their histamine when suspended in a NaC1-containing medium. Depleted granules could be refilled with histamine by suspension in a histamine-containing medium and again depleted of the amine by exposure to sodium chloride. The proposal is made that the histamine release induced by compound 40/80 is a two stage process, a primary energy-requiring transport of histamine-containing granules to the outside of the mast cell and a secondary nonenergy-requiring physico-chemical process, an extracellular cation exchange in the shed granules between histamine and cations, mainly sodium in the tissue fluid.