Adenosine is a well‐described anti‐inflammatory modulator of immune responses within peripheral tissues. Extracellular adenosine accumulates in inflamed and damaged tissues and inhibits the effector functions of various immune cell populations, including CD8 T cells. However, it remains unclear whether extracellular adenosine also regulates the initial activation of naïve CD8 T cells by professional and semi‐professional antigen‐presenting cells, which determines their differentiation into effector or tolerant CD8 T cells, respectively. We show that adenosine inhibited the initial activation of murine naïve CD8 T cells after αCD3/CD28‐mediated stimulation. Adenosine caused inhibition of activation, cytokine production, metabolic activity, proliferation and ultimately effector differentiation of naïve CD8 T cells. Remarkably, adenosine interfered efficiently with CD8 T‐cell priming by professional antigen‐presenting cells (dendritic cells) and semi‐professional antigen‐presenting cells (liver sinusoidal endothelial cells). Further analysis of the underlying mechanisms demonstrated that adenosine prevented rapid tyrosine phosphorylation of the key kinase ZAP‐70 as well as Akt and ERK1/2 in naïve αCD3/CD28‐stimulated CD8 cells. Consequently, αCD3/CD28‐induced calcium‐influx into CD8 cells was reduced by exposure to adenosine. Our results support the notion that extracellular adenosine controls membrane‐proximal T‐cell receptor signalling and thereby also differentiation of naïve CD8 T cells. These data raise the possibility that extracellular adenosine has a physiological role in the regulation of CD8 T‐cell priming and differentiation in peripheral organs.