Dimers of the nonclassical HLA‐G class I molecule have recently been shown to be active structures that mediate inhibition of NK‐cell cytotoxic activity through interaction with the immunoglobulin‐like transcript (ILT)‐2 inhibitory receptor. However, this has only been proven in trophoblasts and HLA‐G transfectants. Here, we document for the first time the existence of HLA‐G dimers in cancer. Indeed, we identified both surface and soluble HLA‐G dimers in tumor cells and malignant ascites respectively. Interestingly, factors from the tumor microenvironment, such as interferons, enhanced the formation of HLA‐G dimers and increased the protection of tumors from NK cell‐mediated lysis. These data emphasize the impact of HLA‐G conformation on its efficiency at inhibiting the antitumor response and thus favoring tumor progression. In view of these results, the effect of the tumor microenvironment on upregulation of HLA‐G function deserves particular attention when designing cancer immunotherapy protocols.