Background: Human Immunodeficiency Virus (HIV) causes AIDS but the course of clinical disease and outcomes can be variable. Multiple factors influence variability in disease progression which may include immunomodulators such as substance abuse and psychological stress. Methamphetamine (meth) abuse is one of the most widely recognized addictions among drug users. Studies have shown that chronic exposure to meth severely affects the nervous system. In addition chronic stress has also been shown to have detrimental effects on neurological function. These problems pose an even greater concern in the HIV pandemic as numerous drug studies have shown close links between immunodeficiency, meth abuse, social stress and various neuropathies. One of the hallmarks of HIV infection is the depletion of CD4+ T-lymphocytes, which are critical mediators of the adaptive immune system. As a result, gut-associated lymphoid tissue (GALT) which houses the majority of CD4+ T-cells has been identified as a critical target of HIV infection. It is not known whether meth abuse and stress alter the gut mucosal immune system and pathology in HIV infection. We hypothesize that exposure to chronic stress and methamphetamine will accelerate enteropathogenesis in HIV infection through mucosal immune modulation, enhanced viral replication and slow viral clearance. Objective: The main objective of this study was to examine how exposure to methamphetamine and stressful social conditions impact HIV enteropathogenesis through the modulation of gut mucosal immune function and mucosal viral reservoirs by using the Simian Immunodeficiency Virus (SIV) infected rhesus macaque model of AIDS. Methods: Twenty one Indian Rhesus macaques were infected with SIV and placed in four experimental groups: Stable/Saline, Unstable with stress/Saline, Stable/Meth and Unstable with stress/Meth. Immunophenotypic analysis was performed using flow cytometry and viral load analysis was carried out using Real Time PCR. Results: SIV infected rhesus macaques exposed to both meth and stress exhibited a higher viral set point and slower viral decay in GALT as a group than that of singly exposed monkeys to either meth or stress during chronic stage of infection. Gut mucosal CD8+ T-cells from animals exposed to the combination of meth and stress exhibited diminished Interferon gamma (IFNg) production and accentuated Interleukin (IL)-17 responses to mitogenic stimulation. Conclusion: This is the first study to report that social stress coupled with meth dampens gut mucosal immune cell function leading to high viral replication and slowing of viral clearance.