From the outset of the HIV epidemic it became clear that the virus capitalized on the immune defenses of the host to create an immune environment that would further foster availability of cellular targets and viral replication. Several studies in animal models of SIV and in humans at various stages of disease have concluded that immune activation represents an independent prognostic factor in HIV including treated disease with successful virologic suppression. Systemic inflammation and immune activation in HIV have been linked to excess risk for both AIDS and non-AIDS serious events in both untreated and treated people living with HIV (PLWH), and seem to accelerate the detrimental effect of other comorbidities such as smoking or diabetes or aging. In addition, inflammation and cellular activation can be critical in viral persistence contributing to the preservation, expansion or population shifts of the HIV viral reservoirs. The etiology of immune activation and inflammation in treated HIV is considered multifactorial encompassing residual viral replication, mucosal injury at effector sites that leads to innate immune activation and potentially dysbiosis, incomplete CD4 restoration, tissue fibrosis and coinfections. Inflammation and fibrosis in HIV are also accompanied by coagulopathy. Biomarkers that signify the degree of inflammation such as IL-6, CRP, sCD14 as well as D-dimer levels have been found in numerous studies to be strong independent predictors of morbidity and mortality in PLWH. It is though unclear if and to what extent, altering these biomarkers with anti-inflammatory or other therapies could alter clinical outcomes. Efforts to counteract the chronic inflammation in HIV have focused on the various facets of its etiology largely with small or moderate success. At the moment the best approach is treatment with antiretroviral therapy, preferably at diagnosis at early stages of disease when CD4 counts are still high, in combination with aggressive treatment of possible comorbidities. A better understanding of the etiologic pathways and how they intersect leading to chronic inflammation in HIV will be critical for improved, and efficacious, treatment interventions.