While the hallmark of HIV-1 infection is the progressive depletion of CD4(+) T cells, extensive B-cell dysfunction ensues that impairs the quality of the humoral response. HIV-1 infection causes hypergammaglobulinemia, polyclonal activation, loss of memory B-cell subsets, B-cell exhaustion, aberrant B-cell surface markers, and impaired humoral responses against infections and vaccinations. The totality of the mechanisms that contribute to B-cell dysfunction in vivo is unknown, although roles for HIV proteins (Env, Tat, and Nef) and virions binding to CD21 on B cells have been identified. Recent studies suggest that early antiretroviral therapy, that minimizes virus replication, can profoundly preserve the early B-cell response to HIV-1. Thus, it is clear that there is an intricate interplay between HIV replication and stimulation of the host B-cell response to infection. A better understanding of how HIV-1 subverts a productive B-cell response is needed to inform vaccine strategies that aim to elicit long-lived plasma cells and memory B-cell responses that can act quickly upon antigen stimulation.