Cells spontaneously secreting IgG or IgM (ISC) are present at a high level in the blood of patients with systemic lupus erythematosus (SLE). By use of magnetic‐bead techniques, mononuclear cells from such patients and healthy donors were fractionated according to expression of CD19 or CD38 and the cell fractions were then cultured in the absence of added mitogen/antigen for 5/6 days. Supernatant IgG and IgM were determined and, in addition, in the CD38 experiments ISC were enumerated both before and after culture. Much of the immunoglobulin‐producing capacity of unfractionated cells (UFC) from both donor groups was recovered in the CD19⁻ fraction, and no immunoglobulin was produced by CD19⁺ cells suggesting, unexpectedly, that ISC were not expressing CD19. By contrast, CD38 fractionation resulted in nearly all ISC passing to the CD38⁺ fraction which produced levels of immunoglobulin approaching 50% that of UFC. On culture of CD38⁻ cells there was a build up in the number of IgG and IgM ISC, this being particularly striking in the controls with numbers well in excess of those in UFC. Not all these new ISC became CD38⁺, but the maturation process was more efficient in the SLE patients. The possibility is discussed that the spontaneous response in the CD38⁻ populations is due to removal of CD38⁺ natural killer (NK) cells. Removal of ISC that are present preculture is a helpful initial step in studying ISC generation in the disease.