Background: For borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC), upfront surgery was standard in the past, and the usefulness of neoadjuvant treatment (NAT) has been reported in recent years. However, few studies have been conducted to date on whether there is a difference in optimal treatment between BR-PDAC invading the portal vein (BR-PV) or abutting major arteries (BR-A). The objective of this study was to investigate the optimal treatment for BR-PV and BR-A. Methods: We retrospectively analyzed 199 patients with BR-PDAC (88 BR-PV and 111 BR-A). For each BR-PV and BR-A, we analyzed the following points. 1) Comparison of prognosis of upfront surgery vs. NAT, 2) Comparison of regimens in patients who underwent NAT, 3) Prognostic factors in patients who underwent resection after NAT. Results: 1) In BR-PV patients who underwent upfront surgery (n = 46)/NAT (n = 42), survival was significantly better in the NAT group (3-year overall survival (OS): 5.8%/35.5%, p = 0.004). In BR-A patients who underwent upfront surgery (n = 48)/NAT (n = 63), survival was also significantly better in the NAT group (3-year OS:15.5%/41.7%, p< 0.001). 2) The prognosis tended to be better in patients who received newer chemotherapeutic regimens, such as FOLFIRINOX and gemcitabine with nab-paclitaxel than older regimens such as gemcitabine and/or S-1, in each BR-PV and BR-A patients. The R0 rate was significantly higher (100%) when radiotherapy was used in combination with chemotherapy, regardless of the chemotherapeutic regimen. 3) In 36 BR-PV patients who underwent surgery after NAT, univariate analysis revealed that normalization of tumor marker levels (p = 0.028) and preoperative high prognostic nutritional index (PNI) (p = 0.022) were significantly associated with a favorable prognosis. In 39 BR-A patients who underwent surgery after NAT, multivariate analysis revealed that preoperative PNI > 42.5 was an independent prognostic factor (hazard ratio: 0.15, p = 0.014). The length of NAT was not a prognostic factor for either BR-PV or BR-A. Conclusions: NAT using newer chemotherapy is essential for improving the prognosis of BR pancreatic cancer. These findings suggest that prognosis may be improved by maintaining good nutritional status during preoperative treatment, not by the length of preoperative treatment. In addition, surgery after normalization of tumor markers levels by preoperative treatment contributes to the prolongation of survival.