Previous data suggest that natural anti-Galα1,3Gal (Gal) antibody (Ab) is produced by mature plasma cells. As thalidomide is effectively used in the treatment of patients with multiple myeloma, its effect on natural anti-Gal Ab production has been assessed in two baboons. During a 10-week course of thalidomide administration (until it reached toxic levels in one baboon), there was no major reduction in Ab levels or in their rate of return after a course of extracorporeal immunoadsorption. A significant reduction of CD3+ cells (75%), and particularly of CD4+ cells (65 to 95%), was measured in the blood by flow cytometry. This was associated with general hyporesponsiveness on mixed lymphocyte reactivity in one baboon, but not in the other. Thalidomide would appear to have little effect on the production of natural Ab, but these observations lend some support to previous work by others indicating that thalidomide may suppress the cellular response to an allograft or xenograft.