CD91 molecule is a multifunctional receptor of alpha 2-macroglobulin, heat-shock proteins and calreticulin. CD91 has been implicated in cross-presentation of peptides chaperoned by these proteins to MHC molecules, thus eliciting antigen-specific immune responses. Hence, CD91 is considered as a major regulator of innate and acquired immune responses. Herein, we show that CD91 molecules are expressed by human salivary gland epithelial cells (SGEC), as indicated by immunohistochemical studies in minor salivary gland biopsy tissues (n = 21) as well as by the analyses of human long-term cultured non-neoplastic SGEC lines (n = 11) and the neoplastic HSG cell line. In these cell lines CD91 expression was evaluated by RT-PCR, flow cytometry and confocal microscopy. Standard internalization assays revealed that HSG and SGECs are capable to bind and internalize the CD91 ligand alpha 2-macroglobulin. This internalization is specific, as attested by inhibition studies using unlabeled alpha 2-macroglobulin and a blocking antibody against human CD91 receptor. Conclusively, our findings indicate that SGEC functionally express CD91 receptor, suggesting that this pathway might be involved in the presentation of exogenous antigens in SGEC.