Background: Median overall survival (OS) time of patients with unresectable PC varies widely. Diagnostic tools are presently lacking to predict outcomes. The majority of pancreatic tumors have KRAS mutations. The study aim was to evaluate the utility of baseline and serial measurements of ctDNA KRAS mutation load, alone or in combination with serum CA 19-9, as an outcome prognostic biomarker in patients with unresectable PC undergoing palliative chemotherapy. Methods: In the Danish BIOPAC prospective biomarker study, plasma was collected from 182 unresectable PC patients (85 females, 97 males, median age 68, range 45-89 years; locally advanced disease n = 48; metastatic n = 134) undergoing treatment with gemcitabine (n = 151) or FOLFIRINOX (n = 31). ctDNA KRAS G12/13 mutation levels in archival ( ≤ 6 years) plasma was assessed with enrichment PCR followed by next generation sequencing and standardized reporting of copies per 10⁵ genome equivalents (GE). Results: In a prospective-retrospective study of 182 patients, interim analysis of ctDNA KRAS was conducted (after 168 deaths). 176 of 182 patients had evaluable baseline plasma samples. Of 176 patients, 143 (81%) had > 1 copy mutant KRAS G12/13 ctDNA at baseline. To assess associations between KRAS, CA 19-9 and OS, KRAS and CA 19-9 values were dichotomized by finding thresholds maximizing similarity of OS in each group (thresholds: 41 KRAS copies/10⁵ GE; 314 U/ml, CA 19-9). Both KRAS and CA 19-9 negatively predicted OS (Cox proportional hazards model). KRAS with CA 19-9 was a stronger predictor of death than either marker alone. The hazard rate (HR) of death for patients with KRAS > 41 c/10⁵GE and CA 19-9 > 314 U/ml was 3.0 times as high (95% CI: 2.0 to 4.6) as those with KRAS < 41 c/10⁵GE and CA 19-9 < 314 U/ml. This is compared to HR 2.1 (95% CI: 1.5 to 2.8) for patients with high KRAS vs low KRAS, and HR 1.8 (95% CI: 1.3 to 2.6) for patients with high CA 19-9 vs low CA 19-9. Shorter OS tend to associate with elevated KRAS and CA 19-9 during chemotherapy. Conclusions: Combination of pre-treatment plasma ctDNA KRAS mutation load and CA 19-9 is a strong prognostic factor in patients with unresectable PC receiving palliative treatment with gemcitabine or FOLFIRINOX.