Shortly after the onset of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980s, reports of radiation-associated toxicity in patients with the human immunodeficiency virus (HIV) and AIDS began to appear in the medical literature. Although the majority of reports have focused on AIDS-defining malignancies such as Kaposi sarcoma, greater-than-expected toxicity after a course of radiotherapy or chemoradiotherapy has also been documented in cancers not generally classified as being related to HIV. With improved antiretroviral therapies, HIV patients are living longer and have the potential to develop a variety of HIV-associated and nonassociated malignancies that require treatment, including radiotherapy. This review reports the published data regarding the interactions of HIV, AIDS, and antiretroviral therapy with radiotherapy and implications for the management of malignancies in patients with HIV.