The surfaces of oral mucosa are protected from infections by antimicrobial proteins and natural immunoglobulins that are constantly secreted in saliva, serving as principal innate immune defense in the oral cavity. MyD88 is an important adaptor protein for signal transduction downstream of Toll-like receptors and TACI, receptors for regulation of innate immunity and B cell responses, respectively. Although MyD88-mediated signaling has a regulatory role in the intestinal mucosal immunity, its specific role in the oral cavity has remained elusive. In the present study, we assessed the influence of MyD88 deficiency on the oral innate defense, particularly the expression of antimicrobial proteins in salivary glands and production of salivary basal immunoglobulins, in mice. Microarray analysis of the whole tissues of submandibular glands revealed that the expression of several genes encoding salivary antimicrobial proteins, such as secretory leukocyte peptidase inhibitor (SLPI), S100A8, and lactotransferrin, was reduced due to MyD88 deficiency. Histologically, SLPI-expressing acinar cells were evidently decreased in the glands from MyD88 deficient mice compared to wild-type mice. Flow cytometric analysis revealed that B cell populations, including B-1 cells and IgA+ plasma cells, residing in submandibular glands were increased by MyD88 deficiency. The level of salivary anti-phosphorylcholine IgA was elevated in MyD88 deficient mice compared to wild-type mice. Thus, this study provides a detailed description of the effect of MyD88 deficiency on expression of several salivary antimicrobial factors in mice, illustrating the role for MyD88-mediated signaling in the innate immune defense in the oral cavity.