A number of pathogenic events occurring immediately after the transmission of HIV lead to the establishment of chronic infection. In fact, despite the detection of vigorous virus-specific immune responses during primary infection, HIV is able to establish chronic infection in most of the cases. This is the result of several virologic and immunologic mechanisms that HIV has evolved to escape and/or to weaken virus-specific immune responses. Lymphoid organs represent the primary anatomic site for the establishment of chronic infection, and if highly active antiretroviral therapy is not initiated in early stage disease, there is a progressive destruction of lymphoid tissue that ultimately leads to the profound immunosuppression typical of AIDS. Therefore, analysis of lymphoid organs is crucial for the correct evaluation of the effectiveness of antiretroviral therapy in HIV infection.