HIV establishes a chronic and latent infection that is not eliminated by the host immune defences. The virus induces extensive damage to the immune system, through virus-related and indirect pathogenic mechanisms. Both the cellular and the humoral arms of the immune system are unable to control the infection, which ultimately results in severe exhaustion of several lymphocyte functions and increased susceptibility to secondary and opportunistic infections. A striking pathological feature induced by the persistent viral replication is the aberrant activation of cells of the immune system. Among these cells, B lymphocytes are severely damaged and show signs of phenotypic and functional alterations. In parallel to the polyclonal B cell activation and hypergammaglobulinemia, B cells from patients show impaired reactivity to immunisation and in vitro activation signals. In addition, B lymphocytes from HIV-infected subjects are primed for apoptosis. The role of protective humoral immunity in the control and clinical progression of HIV infection is still much debated and controversial. The aim of the present review is to discuss the mechanisms involved in the loss of B cell functions during HIV infection. In particular, we discuss the role that T and B cell immune activation plays for B cell polyclonal activation and loss of memory B lymphocytes. The current knowledge on B cell damage is also discussed in the context of anti-HIV therapeutic treatment.