Pathogenesis of colorectal cancer (CRC) is accompanied by significant changes in the immune system. However, the role of the adenosine-A2AR-mediated immunosuppressive pathway in oncogenesis and more specifically, the expression of ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1, also known as CD39) remains unclear. The aim of this work was to study the role of СD4⁺ Т cells, most importantly CD39-expressing regulatory T cells (Tregs) in the formation of immune suppression in CRC and in patients with acute pancreatitis (AP). Expression of CD39 by peripheral blood lymphocytes and tumor-infiltrating lymphocytes (TILs) was measured by flow cytometry. The levels of CD39 messenger RNA (mRNA) in the peripheral blood leukocytes were determined by real-time PCR. Our study reveals that patients with CRC accumulate peripheral CD4⁺CD39⁺ cells in the advanced stages of the disease. The proportion of CD39-expressing CD4+ Т cells in the total pool of TILs was higher than in the peripheral blood of the same patients. Tregs of both peripheral blood and tumor specimens of CRC patients showed increased CD39 expression. We have found reliable correlations between the levels of CD4⁺CD39⁺ T cells and the parameters of cell-mediated immunity in CRC patients. Also, CD39 mRNA levels gradually increased during CRC progression. In contrast, patients with AP have the same levels of CD39 mRNA and peripheral blood CD4⁺CD39⁺ Т cells as the controls. Finally, we conclude that activation of CD4⁺CD39⁺ Т cells has an important role in oncogenesis and needs to be studied further.