Mutation of the human immunodeficiency virus by host cells inhibits viral dissemination by creating nonfunctional variants. However, viral mutation does not always eliminate the ability of the virus to disseminate and, in fact, is thought to promote persistence by generating functional mutants that evade immunity or drugs. How and where HIV mutates is not known. Accordingly, where and to what extent variants emerge may be determined by the cell type with optimal mutation apparatus as well as by the properties of the viral genomic sequence itself. Here we considered that HIV, which can infect B cells, may co-opt the Ig somatic hypermutation machinery to generate functional variants and asked whether the HIV envelope coding sequence can diversify in B cells. We show that an HIV envelope coding sequence transfected into B cells mutates in a manner consistent with somatic hypermutation, causing the production of viral protein variants. This result demonstrates that B cells can express and diversify HIV proteins. Thus, B cells may contribute to viral evasion and to the development of multi-drug resistance.