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 sequencing of bacterial small subunit ribosomal RNA (16S rRNA) gene, we characterized the salivary microbiota of patients with pancreatic cancer and compared them to healthy patients and patients with digestive or nondigestive diseases. A total of 146 patients were enrolled at the UCSD Moores Cancer Center where saliva and demographic data were collected from each patient. Of these, we analyzed the salivary microbiome of 108 patients: 8 had been diagnosed with pancreatic cancer, 13 with pancreatic disease, 53 with digestive diseases (including cancer), 12 with non-digestive diseases (including non-digestive cancer) and 22 were classified as nondiseased (healthy) controls. Bacterial 16S rRNA sequences were amplified directly from salivary DNA extractions and subjected to high-throughput sequencing (HTS). We found significant differences in the abundances of several bacterial genera between patients with pancreatic cancer and patients in other categories, including Porphyromonas, Haemophilus, and Campylobacter. In particular, we found the bacterial ratio of Leptotrichia to Porphyromonas was consistently higher in pancreatic cancer patients compared to those with pancreatic disease, other digestive diseases and healthy controls. Interestingly, we did not find lower abundances of Neisseria elongata and Streptococcus mitis or higher numbers of Granulicatella adiacens reported previously using microarray methods. While salivary bacterial biomarkers appear promising, larger sample studies and repeat sampling of individuals are needed to confirm the validity of particular markers.