PURPOSE: This study examines the changes of serum levels of CA 19-9 in patients with pancreatic cancer following neoadjuvant irradiation and chemotherapy to define the potential role of this tumor marker in preoperative management of these patients. MATERIALS AND METHODS: Serum CA 19-9 levels were measured in 42 patients before receiving external beam irradiation with concurrent 5-fluorouracil in preparation for laparotomy and Whipple procedure or intraoperative irradiation (IORT). The CA 19-9 levels were determined again after irradiation, and changes were correlated with findings of restaging computed tomography (CT) scan and laparotomy. RESULTS: Following preoperative irradiation, 10 patients (24%) experienced an increase in CA 19-9 levels whereas 29 patients (69%) showed a decrease in CA 19-9. There was no change in the CA 19-9 levels of 3 patients (7%) after treatment. Of the 10 patients with increased CA 19-9 levels after irradiation, 9 (90%) had developed distant metastases or local tumor progression as determined by restaging CT scan or at laparotomy. In contrast, only 6 of 29 patients (21%) with declining CA 19-9 levels after irradiation demonstrated metastases or local tumor progression on restaging CT scan or at laparotomy. The correlation of CA 19-9 increase or decrease with disease progression or control, respectively, was statistically significant (P = 0.009). CONCLUSIONS: Serum CA 19-9 levels may rise or fall during neoadjuvant therapy. A rising CA 19-9 reliably indicates cancer progression while a falling CA 19-9 connotes disease control in the majority of patients. In developing strategies for application of neoadjuvant therapy for pancreatic cancer, monitoring of CA 19-9 appears most useful for the identification of patients who manifest progressive tumor growth and metastasis in spite of this treatment.