IgM(+)IgD(+)CD27(+) B cells from peripheral blood have been described as circulating marginal zone B cells. It is still unknown when and where these cells develop. These IgM(+)IgD(+)CD27(+) B cells exhibit somatic hypermutations (SHMs) in their B cell receptors, but the exact nature of the signals leading to induction of these SHMs remains elusive. Here, we show that IgM(+)IgD(+)CD27(+) B cells carrying SHMs are observed during human fetal development. To examine the role of T cells in human IgM(+)IgD(+)CD27(+) B cell development we used an in vivo model in which Rag2(-/-)gamma(C)(-/-) mice were repopulated with human hematopoietic stem cells. Using Rag2(-/-)gamma(C)(-/-) mice on a Nude background, we demonstrated that development and induction of SHMs of human IgM(+)IgD(+)CD27(+) B cells can occur in a T cell-independent manner.