The prevalence of smoking is increased in the HIV-infected population. Active smoking is independently associated with higher risk of cardiovascular disease and other co-morbidities including malignancies and osteoporosis in HIV. However, the independent contribution of smoking to the heightened inflammation, immune activation, and cardiovascular risk remains unclear. We recently showed that smoking status is independently associated with increased levels of several inflammatory markers, and that higher inflammatory markers are associated with cardiovascular risk, diabetes and AIDS or non-AIDS clinical events in subjects receiving antiretroviral therapy. This application gathers a superb group of experts in HIV disease, vascular inflammation, immunology, vascular imaging, behavioral interventions, and oral microbiome studies to determine whether smoking status and furthermore smoking cessation, affect cardiovascular disease risk in HIV and the mediation effect of heightened inflammation, immune activation, oxidative stress and oral microbiome changes. Understanding the specific contribution of smoking to the heightened inflammation and immune activation in HIV-infected subjects on antiretroviral therapy has the potential to have a significant impact on prevention of HIV co-morbidities including cardiovascular disease.