IgA is the predominant immunoglobulin class in mucosal secretions. Binding and transport of polymeric immunoglobulins (pIgA and IgM) across epithelia is mediated by the polymeric Ig receptor (pIgR) which is expressed on the basolateral surface of secretory epithelial cells. Although an Fc receptor for IgA (FcaR) has been identified on myeloid cells, lymphocytes and mesangial cells, the expression of a FcaR on epithelial cells has not been described. In the present study, we have investigated the binding of IgA to the human intestinal epithelial cell line HT-29/19A, a clone that exhibits features of differentiated small intestinal enterocytes. Using a cell-based ELISA, we demonstrated dose-dependent and saturable binding of HRP-conjugated monomeric IgA (mIgA) to confluent monolayers of HT-29/19A cells. Fifty to 100-fold molar excess of unlabeled IgA1, but not IgG and IgM, competed for the mIgA binding, suggesting that the binding is IgA isotype-specific and is not mediated by the pIgR. Moreover, the lack of competition of asialofetuin for the mIgA binding excludes the possibility that the IgA binding to HT-29 cells is due to the asialoglycoprotein receptor, previously described on human hepatocytes. In addition to mIgA, we demonstrated binding of heat-aggregated IgA, dimeric IgA1 and IgA2, and sIgA. The Fc fragment of IgA inhibited IgA-HRP binding to HT-29 cells with greater efficiency than the F(ab)2 fragment. Finally, we found that FcaR(CD89) was undetectable on HT-29 cells by FACS or RT-PCR. These data suggest that a novel IgA receptor, distinct from the asialoglycoprotein receptor, pIgR and CD89 is constitutively expressed on a human enterocyte cell line. The function of this IgA binding in mucosal immunity remains to be investigated.