Selective immunoglobulin A deficiency (sIgAD) is the most common immunodeficiency in humans. Auto-reactive antibodies to human immunoglobulin A (IgA) are found in the serum of 20-40% of individuals with sIgAD. It is unknown whether these antibodies play a role in the pathogenesis of this immunodeficiency and although the prevailing thought is that they are secondary to the onset of sIgAD, there is very little, if any, support for this notion. Here, we propose that anti-IgA antibodies are in fact responsible for the removal of IgA from serum, and that the inducing antigen is most probably a xenogeneic IgA. This hypothesis is based on data obtained from an sIgAD patient in whom changes in dietary consumption of beef and/or bovine dairy products resulted in changes in anti-IgA levels in the serum. To test the hypothesis, the presence of anti-bovine IgA antibodies was tested by a highly specific enzyme-linked immunosorbent assay in serum samples from IgA-deficient and control individuals. All 13 sIgAD individuals with anti-IgA antibodies had a higher titer against bovine IgA than against human IgA. Of 23 control individuals, a surprisingly high proportion (65%) was also found to have IgG anti-bovine IgA antibodies. These results support the hypothesis that the anti-human IgA antibodies found in IgA-deficient individuals are originally produced against bovine IgA. These antibodies are found in many normal individuals, but only in cases where they cross react with endogenous human IgA, sIgAD may develop.