Purpose: Pancreatic cancer is one of the most devastating diseases with a 5-year survival rate of 3% to 5%. Here, we investigated whether circulating tumor cells (CTC) may predict metastatic spread and survival in pancreatic cancer patients. Experimental Design: In a prospective study, we enrolled 69 pancreatic cancer patients. In peripheral blood, CTCs were identified by MACS enrichment (anti-cytokeratin/anti-EpCam) and subsequent automated analysis after combined anti-cytokeratin/anti-CD45/DAPI staining. CTC results were correlated to established clinicopathologic risk factors, detection of disseminated tumor cells (DTC) in bone marrow, and clinical outcome (follow-up time: 48 months). Results: Median patient survival was 11 months (0–48 months). Thirty-eight patients were male and 31 were female, and the majority received gemcitabine (58/69). CTCs were present in 23 of 69 patients (33.3%) ranging from 1 to 19 cells (17 with 〉1 CTC). Although clinicopathologic parameters and DTC status did not correlate with CTC incidence, progression-free survival (PFS) and overall survival (OS) were significantly reduced in CTC-positive patients in univariate ( P = 0.009, PFS; P = 0.030, OS, both log rank) and multivariate analysis [HR = 4.543; confidence interval (CI), 1.549–13.329; P = 0.006, PFS; HR = 2.093; CI, 1.081–4.050; P = 0.028, OS, both Cox regression). Also within patients receiving chemotherapy, PFS was significantly reduced in CTC-positive patients in univariate ( P = 0.013) and multivariate (HR = 4.203; CI, 1.416–12.471; P = 0.010) analysis. Conclusions: CTCs affect the outcome of patients with pancreatic cancer independent from other risk factors, including patients receiving (adjuvant) cytotoxic therapy. CTC stratification may allow a better upfront identification of patients with a longer lifespan who might profit from new adjuvant therapies. Clin Cancer Res; 24(12); 2844–50. ©2018 AACR .