Interleukin 12 (IL‐12) is a crucial cytokine in the regulation of T helper 1 vs. T helper 2 immune responses. In the present study, we investigated the effect of the endogenous purine nucleoside adenosine on the production of IL‐12. In mouse macrophages, adenosine suppressed IL‐12 production. Although the order of potency of adenosine receptor agonists suggested the involvement of A_2a receptors, data obtained with A_2a receptor‐deficient mice showed that the adenosine suppression of IL‐12 and even TNF‐α production is only partly mediated by A_2a receptor ligation. Studies with adenosine receptor antagonists or the adenosine uptake blocker dipyridamole showed that adenosine released endogenously also decreases IL‐12. Although adenosine increases IL‐10 production, the inhibition of IL‐12 production is independent of the increased IL‐10. The mechanism of action of adenosine was not associated with alterations of the activation of the p38 and p42/p44 mitogen‐activated protein kinases or the phosphorylation of the c‐Jun terminal kinase. Adenosine failed to affect steady‐state levels of either IL‐12 p35 or p40 mRNA, but augmented IL‐10 mRNA levels. In summary, adenosine inhibits IL‐12 production via various adenosine receptors. These results support the notion that adenosinebased therapies might be useful in certain autoimmune and/or inflammatory diseases.—Haskó, G., Kuhel, D. G., Chen, J.‐F., Schwarzschild, M. A., Deitch, E. A., Mabley, J. G., Marton, A., Szabó, C. Adenosine inhibits IL‐12 and TNF‐a production via adenosine A_2a receptor‐dependent and independent mechanisms. FASEB J. 14, 2065–2074 (2000)