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−/−γC−/− mice were repopulated with human hematopoietic stem cells. Using Rag2−/−γC−/− 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.