Clinical manifestations of pancreatic cancer often do not occur until the cancer has undergone metastasis resulting in a very low survival rate. In this study, we investigated whether salivary bacterial profiles might provide useful biomarkers for early detection of pancreatic cancer. Using high-throughput bacterial small subunit ribosomal RNA (16S rRNA) gene sequencing, we characterized the salivary microbiota of patients with pancreatic cancer and compared them to healthy patients, and patients with digestive and non-digestive diseases. A total of 146 patients were enrolled at the UCSD Moores Cancer Center and saliva, buccal swabs, and patient demographic data were collected from each patient. Of these, we analyzed the salivary microbiome of 108 patients, 8 diagnosed with pancreatic cancer, 13 with pancreatic disease, 53 with digestive disease (including cancer), 12 with a non-digestive disease (including non-digestive cancer) and 22 were non-disease (healthy) controls. 16S rRNA genes were amplified directly from salivary DNA extractions and subject to high-throughput sequencing (HTS). After sequence quality assessment and sequencing depth normalization, we found significant differences in the absolute abundances of several bacterial species, including Porphyromonas, Haemophilus, and Campylobacter between patients with pancreatic cancer and patients in other categories. In particular, we found the ratio of Leptotrichia to Porphyromonas bacteria was consistently higher in pancreatic cancer patients compared to pancreatic disease, other digestive diseases and healthy controls. This ratio also discriminated between pancreatic cancer and other diseases commonly misdiagnosed as pancreatic cancer. Our results suggest that culture-independent analysis of salivary bacteria holds promise for early detection of pancreatic cancer.