The effects of adenosine and subtype-specific activators of adenosine receptors (A₁, A_2A, A_2B and A₃) were studied on the release of interleukin-1β (IL-1β) from peripheral mononuclear cells, monocytes and lymphocytes. In the cells activated by the protein kinase C specific phorbol ester (phorbol 12-myristate 13-acetate) and Ca²⁺ ionophore (A23187) both adenosine and the subtype-specific receptor agonists, CPA (A₁), CGS 21680 (A_2A) and IB-MECA (A₃) induced a concentration-dependent inhibition of IL-1β release. The rank order of potency in the inhibition of IL-1β release was CPA=CGS 21680>IB-MECA>adenosine>NECA (in the presence of A₁, A_2A and A₃ receptor inhibitors). The inhibitory actions of CPA, CGS 21680 or IB-MECA were significantly reduced in the presence of DPCPX, ZM 243185 or MRS 1191 as subtype-specific antagonists on A₁, A_2A and A₃ adenosine receptors, respectively. It can be concluded that adenosine inhibits the release of IL-1β from the activated human peripheral mononuclear cells. In this process A₁, A_2A and A₃ receptors are involved.