<p>Esophageal cancer is the eighth most common cancer, the third most common gastrointestinal cancer, and the leading cause of cancer death worldwide. Adenosine receptor signaling is one of the important pathways that have been recently found to be dysregulated in some cancers. Adenosine receptors are divided into four subgroups: A1, A2a, A2b, A3, and here in the current study, we aimed to investigate their association with esophageal cancer. The results showed that the expression level of adenosine receptor genes A1, A2a, A2b, and A3 in esophageal tumor tissue was increased 5.02, 4.22, 9.36, and 3.90 times compared to tumor margin tissue, respectively (<i>p</i> &lt; 0.05). According to the comparison of these values, the A2b receptor gene has the highest overexpression in esophageal tumor samples. There was no significant relationship between adenosine receptor gene expression and age, grade, and tumor size of patients with esophageal cancer. Our data also indicated that adenosine-induced cell death was inhibited by the A2B adenosine receptor antagonist (PSB 603). Finally, our results showed an increase in the expression of all four adenosine receptors in tumor tissue relative to the tumor margin, and the pattern of adenosine receptor expression (A2b &gt; A1 &gt; A2a &gt; A3) shows that the A2b receptor is probably more important than the other adenosine receptors regarding the overexpression level and adenosine-mediated cell death in esophageal cancer cells.</p>