Objectives <p>This study aimed to evaluate the predictive value of [¹⁸F]AlF-NOTA-FAPI-04 PET/CT for pathological response to neoadjuvant chemotherapy (NCT) and prognosis in patients with locally advanced pancreatic ductal adenocarcinoma (LAPDAC).</p> Methods <p>This study included 34 patients with histopathologically and radiologically confirmed LAPDAC who received [¹⁸F]AlF-NOTA-FAPI-04 PET/CT scans before NCT. After 4–6 cycles of NCT, these patients underwent radical resection. Pathological response to NCT was assessed by pathological tumor regression grades (TRG) based on the Evans system. PET/CT parameters were evaluated for their association with TRG, recurrence-free survival (RFS) and overall survival (OS) after NCT, including the maximum standardized uptake value (SUV_max), FAPI-avid tumor volume (FTV), total lesion FAP expression (TLF) of primary tumor, total FAPI-avid pancreatic volume (FPV) and total pancreatic FAP expression (TPF) of total pancreas.</p> Results <p>Of 34 patients with LAPDAC, 14 patients had a pathologic good response (PGR, Evans III-IV), and 20 patients had a pathologic poor response (PPR, Evans I-II). Both the primary tumor SUV_max, FTV and TLF, and total pancreas FPV and TPF in the PGR groups were significantly lower than those in the PPR groups. Furthermore, SUV_max and TLF were higher in poorly differentiated LAPDAC than in well-moderately differentiated neoplasms. The FTV, TLF, FPV and TPF were closely associated with RFS and OS. On multivariate analysis, patients with FTV &gt; 54.21 and TLF &gt; 290.21 had a worse RFS and OS, respectively (HR = 3.24, <i>P</i> = 0.014 and HR = 3.35, <i>P</i> = 0.019) and OS (HR = 7.35, <i>P</i> = 0.002 and HR = 7.09, <i>P</i> = 0.004) in LAPDAC after NCT.</p> Conclusions <p>The parameters of [¹⁸F]AlF-NOTA-FAPI-04 PET/CT had the excellent performance for predicting pathologic TRG after NCT in LAPDAC. FTV and TLF were independent postoperative prognostic factors for RFS and OS for LAPDAC.</p>