The advent of combined antiretroviral therapy (cART) has led to a dramatic decline in AIDS-associated mortality. However, as individuals with HIV are aging, their risk of mortality from malignancies has increased, and is now one of the leading cause of mortality among HIV-positive individuals. HIV-infected individuals are exposed to life-long cART, as well as other medications to treat chronic co-morbidities associated with cART and aging. However, there have been no studies that have evaluated the individual effects of specific classes of cART medication, and other long-term medications on cancer incidence while measuring the mediating effect of metabolic disease, while adjusting for other known risk factors in patients with well-controlled HIV infection. In response to Provocative Question 3 and to address this gap in knowledge, we propose the following specific aims to determine the impact of specific chronic medication classes on the incidence of eight common non-AIDS defining Cancers (NADC)s: lung cancer, non-oropharynx head and neck, colorectal, and prostate cancers, as well as Hodgkin's Lymphoma, squamous cell cancer of the anus (SCCA), oropharynx cancer, and Hepatocellular carcinoma utilizing a large retrospective cohort study of individuals with well- controlled HIV infection. AIM 1: a) To measure the effect of the duration of specific classes of cART medications on the risk of each of the 8 NADCs of interest in a cohort of veterans with well-controlled HIV, adjusting for known risk factors for each type of cancer, and b) to assess the extent of cancer risk that is mediated by metabolic disorders. AIM 2: a) To measure the effect of duration of specific classes of common medications used to treat metabolic disorders known to impact cancer risk, utilized by HIV-infected individuals (e.g., statins, metformin, beta-blockers and ACE-Inhibitors) on the risk of developing the 8 NADCs of interest in a cohort of veterans with well-controlled HIV-infection; and b) to assess the extent that the observed cancer risk association from these common metabolic disorder-related medication is primarily mediated through their impacts on metabolic disorder control. The current proposal will specifically address Provocative Question 3, by measuring the direct impact of specific medication classes on NADC risk as well as the potential mediating effect of metabolic diseases on this risk in a large well-controlled HIV-infected cohort. As a result of this proposal, we will be able to identify novel mechanisms to modulate cancer risk associated with medication utilization, and to identify potential novel pharmacologic approaches for cancer prevention in patients living with chronic HIV disease.