Cancer is a major cause of death worldwide. These include breast, pulmonary, colorectal, and prostate. It is known that cancer is caused by lifestyle such as diet, alcohol, and cigarette consumption and that one-third of cancer deaths are due to these factors. In addition to these drivers, several genes have been shown to be involved in the development and outcome of cancer. One of these genes is the major histocompatibility complex (MHC) gene, which codes for human leukocyte antigens (HLA), which play an important role in the immune system. Recently, the possible role of the non-classical HLA-class-I molecule HLA-G, which has different isoforms, in cancer development by affecting cancer immunity has become the focus of researchers’ attention. In many studies, HLA-G has been claimed to be a novel mechanism of tumor escape in solid tumors. In this chapter, the characteristics and potential role of HLA-G in several types of solid cancers are discussed.