We have identified a distinct pre-naive B cell population circulating in human peripheral blood that exhibits an intermediate phenotype between transitional and naive B cells. Like human transitional B cells, these cells express CD5 but have intermediate densities of CD38, CD10, CD9, and the ABCB1 transporter compared with transitional and naive B cells. These pre-naive B cells account for a majority of circulating human CD5(+) B cells. Importantly, CD5(+) pre-naive B cells could be induced to differentiate into cells with a naive phenotype in vitro. CD5(+) pre-naive B cells show only partial responses to BCR stimulation and CD40 ligation and undergo more spontaneous apoptosis and cell death than do naive B cells, whereas BAFF/BLyS (B cell-activating factor belonging to the TNF family) did not enhance their survival compared with naive B cells. In contrast, CD5(+) pre-naive B cells carry out certain functions comparable to naive B cells, including the capacity to differentiate into plasma cells and the ability to function as APCs. Notably, an increased proportion of CD5(+) pre-naive B cells were found in peripheral blood of patients with systemic lupus erythematosus. These results have identified a unique intermediate in human naive B cell development within the peripheral blood and derangements of its homeostasis in patients with systemic lupus erythematosus.