The survival period of human immunodeficiency virus (HIV)-infected patients has been gradually extended due to effective combination antiretroviral therapy. The immune response of HIV-infected individuals also plays a crucial role in the recovery of the host’s immune system during viral suppression phase. HIV infection activates the interferon signaling pathway and induces up-regulated expression of interferon-stimulated genes (ISGs) that exert antiviral effects. The ubiquitin-like protein ISG15 is one of the most significantly up-regulated host factors in HIV-infected patients, inhibiting the budding and release of HIV viral particles through ISGylation, while the non-structural proteins of HIV interfere with ISGylation process or bind to key molecules of interferon signaling pathways to reverse the inhibitory effect of ISG15 on the virus. Herein we review the biological characteristics of ISG15, its expression in different cell populations, antiviral effects, and mechanism of escaping from the host immune restriction, in order to further understand the role of ISG15 in HIV infection, and to explore the opportunities of functional cure of HIV-infected patients with the strategies using host factors.