Background: Pancreatic cancer is a lethal malignancy and patients often survive within one year. CA19-9 is the most important biomarker for pancreatic cancer and Lewis (-) individuals have no or scarce CA19-9 secretion. We have met several patients with low CA19-9 and metastatic disease survived over one year without major treatments, prompted us to examine the characteristics of CA19-9-Low subgroup (Lewis (+)&CA19-9 ≤ 37 U/mL). Methods: Medical record of 1484 patients was retrieved from a prospectively maintained database. Lewis genotypes were determined by Sanger sequencing. Characteristics of CA19-9-Low pancreatic cancers were examined. Results: No significant difference was found between Lewis (-) (8.4%) and CA19-9-High (77.8%) patients in survival (HR = 1.16, P = 0.216). CA19-9-Low patients (13.8%) had strikingly better survival than CA19-9-High&Lewis (-) patients (HR = 0.52, P < 0.001). The 5-year survival rate of stage III, IV CA19-9-Low patients (28.2%) was even higher than that of stage I, II CA19-9-High&Lewis (-) patients (21.5%). Compared with CA19-9-High&Lewis (-) patients, CA19-9-Low patients had a lower proportion of nerve invasion (74.7% vs. 84.2%, P = 0.044), EGFR expression (37.5% vs. 51.2%, P = 0.047), a lower level of serum glucose (6.3 ± 1.9 vs. 7.4 ± 3.1, P = 0.001) and neutrophil-lymphocyte ratio (2.6 ± 2.4 vs.3.0 ± 3.1, P = 0.027), and poor response to Gemcitabine-based chemotherapy (stage I, II, HR = 0.73, P = 0.446; stage III, IV, HR = 0.70, P = 0.244). Conclusions: CA19-9-Low pancreatic cancer is a unique subtype with poor response to Gemcitabine-based chemotherapy.