Background: Several studies have linked a decrease of carbohydrate antigen (CA) 19-9 to lengthened survival in pancreatic cancer. Experimental evidence supported that CA19-9 may be involved in platelet/tumor cell interactions. The object of this study was to correlate a decline in CA19-9 with survival according to platelet level in metastatic pancreatic cancer. Methods: A retrospective analysis of patients with histologically diagnosed metastatic pancreatic cancer was performed. CA19-9 serum concentration and platelet level was measured at baseline and every 6 weeks. Results: Total 174 metastatic pancreatic cancer patients with baseline and week-6 CA19-9 measurements were analyzed. Median follow-up from initial chemotherapy was 29.2 months, and median survival from initial chemotherapy was 6.7 months. Multivariate analyses confirmed an early decrease in CA19-9 concentrations of 25% after two cycles of chemotherapy were associated with a favorable survival compared with patients who did not have a decrease of 25% (HR = 0.56 [95% CI: 0.40-0.78]). The association of CA19-9 decrease with overall survival differed by platelet level (P_interaction< 0.001). Multivariable adjusted hazard rations for decrease in CA19-9 of 25% were 0.30 (0.18-0.49) in patients with low platelet level (PLT < 190 × 10⁹/L) and 0.85 (0.53-1.35) in patients with high platelet level (PLT ≥ 190×10⁹/L). Conclusions: In patients with MPC, 25% decrease at week-6 could be an early marker for prognosis. The association of CA19-9 decrease with pancreatic cancer survival is stronger in patients with platelet low tumors than platelet high tumors. Our findings suggest a differential prognostic effect of CA19-9 according to platelet level.