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I ndividuals with X-linked lymphoproliferative disease (XLP) display defects in B cell differentiation in vivo. Specifically, XLP patients do not generate a normal number of CD27⁺ memory B cells, and those few that are present are IgM⁺. Recent studies have suggested that IgM⁺CD27⁺ B cells are not true memory cells, but rather B cells that guard against T cell–independent pathogens. Here we show that human XLP IgM⁺CD27⁺ B cells resemble normal memory B cells both morphologically and phenotypically. Additionally, IgM⁺CD27⁺ B cells exhibited functional characteristics of normal memory B cells, including the ability to secrete more Ig than naive B cells in response to both T cell–dependent and –independent stimuli. Analysis of spleens from XLP patients revealed a paucity of germinal centers (GCs), and the rare GCs detected were poorly formed. Despite this, Ig variable region genes expressed by XLP IgM⁺CD27⁺ B cells had undergone somatic hypermutation to an extent comparable to that of normal memory B cells. These findings reveal a differential requirement for the generation of IgM⁺ and Ig isotype–switched memory B cells, with the latter only being generated by fully formed GCs. Production of affinity-matured IgM by IgM⁺CD27⁺ B cells may protect against pathogens to which a normal immune response is elicited in XLP patients.