Adenosine is an endogenous metabolite produced during hypoxia or inflammation. Previously implicated as an anti-inflammatory mediator in CD4+ T cell regulation, we report that adenosine acts via dendritic cell (DC) A 2B adenosine receptor (A 2B AR) to promote the development of Th17 cells. Mouse naive CD4+ T cells cocultured with DCs in the presence of adenosine or the stable adenosine mimetic 5′-(N-ethylcarboximado) adenosine resulted in the differentiation of IL-17–and IL-22–secreting cells and elevation of mRNA that encode signature Th17-associated molecules, such as IL-23R and RORγt. The observed response was similar when DCs were generated from bone marrow or isolated from small intestine lamina propria. Experiments using adenosine receptor antagonists and cells from A 2B AR−/− or A 2A AR−/−/A 2B AR−/− mice indicated that the DC A 2B AR promoted the effect. IL-6, stimulated in a cAMP-independent manner, is an important mediator in this pathway. Hence, in addition to previously noted direct effects of adenosine receptors on regulatory T cell development and function, these data indicated that adenosine also acts indirectly to modulate CD4+ T cell differentiation and suggested a mechanism for putative proinflammatory effects of A 2B AR.