We have previously shown that in addition to the well-known secreted isoform of prostatic acid phosphatase (sPAP), a transmembrane isoform exists (TMPAP) which interacts with snapin (a SNARE associated protein) and regulates the endo-/exocytic pathways. We have also shown that PAP has 5'-ectonucleotidase and thiamine monophosphatase activity, and elicits anti-nociceptive effects in mouse models of chronic inflammatory and neuropathic pain. Therefore, in order to determine the physiological role of PAP in a typical exocrine organ, we studied the submandibular salivary gland (SMG) of PAP-/- and wild-type C57BL/6J mice by microarray analyses, microRNA sequencing, activity tests, immunohistochemistry and biochemical and physiological analyses of saliva. We show that PAP is the main acid phosphatase in the wild-type male mouse saliva, accounting for 50% of the total acid phosphatase activity, and it is only expressed in the granular convoluted tubules of the SMGs, where it is the only 5'-ectonucleotidase. The lack of PAP in the male PAP^-/- mice was associated with a significant increase in the salivation volume under secretagogue stimulation, overexpression of genes related to cell proliferation (Mki67, Aurkb, Birc5) and immune response (Irf7, Cxcl9, Ccl3, Fpr2), and upregulation of miR-146a in SMG. An increased and sustained acinar cell proliferation was detected without signs of glandular hyperplasia. Our results indicate that in PAP^-/- mice SMG homeostasis is maintained by an innate immune response. Additionally, we suggest that in male mice PAP via its 5'-ectonucleotidase activity and production of adenosine can elicit analgesic effects when animals lick their wounds.