Persistent generalized lymphadenopathy (PGL) represents an important aspect of the natural history of AIDS. It is a reactive lymphadenitis appearing in HIV-positive drug abusers and homosexual men, involving lymph nodes mostly located in the neck and in axillary regions. This present review chapter describes the most salient histological and immunohistochemical features of lymph nodes of intravenous drug abusers affected by PGL. Microscopic changes are homogeneous and essentially comparable allowing to subgroup nodes according to their histologic pattern: those with hyperplastic and those with regressive changes. Hyperplastic changes include hyperplasia of germinal centers without or with fragmentation and vascularization, and increased postcapillary venules in the paracortex. Regressive changes are characterized by follicular involution and by follicular depletion with or without fibrosis. Immunohistologic phenotyping shows a peculiar infiltration of CD3/CD8+ lymphocytes in germinal centers and a progressive lysis of follicular dendritic reticulum cells. The presence of HIV antigens can be demonstrated in germinal centers with a reticular pattern paralleling that of follicular dendritic reticulum cells, in endothelial cells of paracortical venules, and in sinus macrophages. Furthermore, HIV genome is sometimes detectable by in situ hybridization in a few endothelial and mononuclear cells of the paracortex. Epstein Barr virus (EBV) antigens are occasionally observed in a few lymph node cells, while EBV genome seems to be absent during the PGL phase of the HIV infection. In conclusion, during PGL, immunohistologic features correlate well with the extent of the histologic changes.