Metabolic intratumoral heterogeneity (ITH) is known to be related to cancer treatment outcome. However, information on the temporal changes in metabolic ITH during chemotherapy and the correlations between metabolic changes and treatment outcomes in patients with pancreatic cancer is sparse. We aimed to analyze the temporal changes in metabolic ITH and the predictive role of its changes in advanced pancreatic cancer patients who underwent palliative chemotherapy. Methods: We prospectively enrolled patients with unresectable locally advanced or metastatic pancreatic cancer before first-line palliative chemotherapy. 18F-FDG PET was performed at baseline and at the first response follow-up. SUVs, volumetric parameters, and textural features of the primary pancreatic tumor were analyzed. Relationships between the parameters at baseline and first follow-up were assessed, as well as changes in the parameters with treatment response, progression-free survival (PFS), and overall survival (OS). Results: Among 63 enrolled patients, the best objective response rate was 25.8% (95% confidence interval [CI], 14.6%-37.0%). The median PFS and OS were 7.1 mo (95% CI, 5.1-9.7 mo) and 10.1 mo (95% CI, 8.6-12.7 mo), respectively. Most parameters changed significantly during the first-line chemotherapy, in a way of reducing ITH. Metabolic ITH was more profoundly reduced in responders than in nonresponders. Multiple Cox regression analysis identified high baseline compacity (P = 0.023) and smaller decreases in SUVpeak (P = 0.007) and entropy gray-level cooccurrence matrix (P = 0.033) to be independently associated with poor PFS. Patients with a high carbohydrate antigen 19-9 (P = 0.042), high pretreatment SUVpeak (P = 0.008), and high coefficient of variance at first follow-up (P = 0.04) showed worse OS. Conclusion: Reduction in metabolic ITH during palliative chemotherapy in advanced pancreatic cancer patients is associated with treatment response and might be predictive of PFS and OS.