Adenosine inhibits immunoglobulin E-dependent histamine release when preincubated with human basophil leukocytes before challenge. Two distinct mechanisms for this inhibition have been demonstrated. The first we suggest to be an A2-purinoceptor mediated mechanism. This effect, which is apparent with both 15- and 60-min preincubation periods, is mimicked by 5'-N-ethylcarboxamideadenosine, blocked by 8-phenyltheophylline but not dipyridamole and is associated with the ability of adenosine to elevate cyclic AMP. The second, which is mimicked by 3-deazaadenosine and is associated only with the longer 60-min preincubation period, is reversed by dipyridamole but not by 8-phenyltheophylline suggesting it to be an intracellular mechanism. Its enhancement by homocysteine thiolactone and reversal by exogenous S-adenosyl methionine suggests it to result from increasing intracellular S-adenosyl homocysteine levels. Our failure to detect increased 3H-methyl incorporation into chloroform-methanol extractable lipids after immunoglobulin E-dependent activation would indicate that inhibition of S-adenosyl methionine methylation reactions are an unlikely mechanism. As both prior stimulation of A2-purinoceptors and elevation of intracellular S-adenosyl homocysteine enhance and prolong the cyclic AMP response consequent upon immunoglobulin E-dependent activation, this represents a common mechanism by which histamine release may be suppressed.