BACKGROUND: Natural-killer group 2 (NKG2), a characteristic receptor of natural killer (NK) cell family, assumes a vital role in modulating NK cytotoxic function. We aimed to detect mRNA expression of both NKG2A and NKG2D in serum NK cells obtained from colorectal cancer (CRC) patients. METHODS: We enrolled 36 patients with newly diagnosed CRC, as well as 15 group matched healthy individuals. The patients were further classified into: 23 non-metastatic CRC (group 1) and 13 metastatic CRC (group 2). We detected the expression of NKG2A and NKG2D serum levels for all participants utilizing real-time polymerase chain reaction (RT-PCR). RESULTS: NKG2D and NKG2A mRNA levels in peripheral blood mononuclear cells (PBMCs) were significantly elevated in patients with CRC compared to controls (P<0.01). NKG2D or NKG2A showed sensitivity (77.8, 83.33%) and specificity (73.33, 100%) respectively using receiver-operating characteristic (ROC) curve analysis for discrimination between patients and controls, whereas group 1 and group 2 showed no statistical significant difference in NKG2D and NKG2A levels (P>0.05). CONCLUSIONS: Our work is one of the first research that could detect an increase in NKG2D in CRC. In spite of their defensive role in tumor immune surveillance, NKG2D and NKG2A and their ligands could have misused as tumor survival tool, empowering immune avoidance and suppression.