No reliable predictive blood-based biomarkers are available for determining survivalfrom pancreatic adenocarcinoma (PDAC). This combined discovery and validation study examinespromoter hypermethylation (ph) of secreted frizzled-related protein 1 (SFRP1) in plasma-derivedcell-free DNA as an independent prognostic marker for survival and Gemcitabine effectiveness inpatients with stage IV PDAC. We conducted methylation-specific polymerase chain reaction analysisof the promoter region of the SFRP1 gene, based on bisulfite treatment. Survival was analyzed withKaplan–Meier curves, log-rank test, and Cox regression. The discovery cohort included 40 patients,25 receiving Gem. Gem-treated patients with phSFRP1 had a shorter median overall survival (mOS)(4.4 months) than unmethylated patients (11.6 months). Adjusted Cox-regression yielded a hazardrate (HR) of 3.48 (1.39–8.70). The validation cohort included 58 Gem-treated patients. Patientswith phSFRP1 had a shorter mOS (3.2 months) than unmethylated patients (6.3 months). AdjustedCox regression yielded an HR of 3.53 (1.85–6.74). In both cohorts, phSFRP1 was associated withpoorer survival in Gem-treated patients. This may indicate that tumors with phSFRP1 are moreaggressive and less sensitive to Gem treatment. This knowledge may facilitate tailored treatment ofpatients with stage IV PDAC. Further studies are planned to examine phSFRP1 in more intensivechemotherapy regimens.