Human neutrophils have been demonstrated to possess both adenosine A1 and A2 receptors: activation of adenosine A2 receptors inhibits the respiratory burst, assayed as superoxide anion production (O-2) from cells stimulated by the bacterial peptide N-formylmethionyl-leucyl-phenylalanine (FMLP). Exposure of neutrophils to different combinations of stimuli results in synergistic or primed responses. These responses can be measured by challenging the cells either with a combination of FMLP and platelet activating factor (PAF), or with a combination of PAF and the neuropeptide substance P, which by itself does not induce O-2 production. In order to evaluate the ability of adenosine receptor agonists to inhibit O-2 production by primed or synergistically stimulated neutrophils, a non-selective adenosine receptor agonist, 2-chloroadenosine, was tested in comparison with reportedly selective ligands of adenosine A1 and A2 receptor types, N6-cyclopentyladenosine (CPA) and 2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethyl-carboxamido adenosine (CGS 21680). The order of activity CGS 21680 > 2-chloroadenosine > CPA indicates that adenosine A2 receptors mediate the inhibition of the respiratory burst even when neutrophils are primed or synergistically activated. 8-Phenyltheophylline antagonized the effects of these adenosine receptor agonists in a competitive way.