Human T cell leukemia virus type 1 (HTLV-1) is the first human oncogenic retrovirus to be discovered and causes two major diseases: a progressive neuro-inflammatory disease, termed HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), and an aggressive malignancy of T lymphocytes known as adult T cell leukemia (ATL). Innate and acquired immune responses play pivotal roles in controlling the status of HTLV-1-infected cells and such, the outcome of HTLV-1 infection. Natural killer cells (NKCs) are the effector cells of the innate immune system and are involved in controlling viral infections and several types of cancers. The ability of NKCs to trigger cytotoxicity to provide surveillance against viruses and cancer depends on the balance between the inhibitory and activating signals. In this review, we will discuss NKC function and the alterations in the frequency of these cells in HTLV-1 infection.