Abstract Background The survival benefit of adjuvant chemotherapy (AC) for pancreatic ductal adenocarcinoma (PDAC) after neoadjuvant therapy (NAT) and resection remains controversial. Previous studies often pooled diverse disease stages or chemotherapy regimens, potentially obscuring regimen-specific outcomes. We sought to investigate the association of AC with overall survival (OS) among patients with resected borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), stratified by specific neoadjuvant and adjuvant regimens. Methods This multinational, retrospective cohort study included 834 patients with BRPC/LAPC who underwent curative-intent resection following NAT with either FOLFIRINOX or gemcitabine plus nab-paclitaxel (Gem/Nab). Propensity score matching (1:1) was utilized to minimize selection bias. The primary outcome was OS, analyzed using Kaplan-Meier methods and Cox proportional hazards models. Results Among 834 patients, 605 received neoadjuvant FOLFIRINOX and 229 received neoadjuvant Gem/Nab. In the matched analysis for the neoadjuvant FOLFIRINOX cohort, continuation of adjuvant FOLFIRINOX was associated with longer OS compared with no AC (median OS, 42.0 vs. 25.8 months; HR, 0.58; 95% CI, 0.43-0.79; p < 0.001). In contrast, switching to adjuvant Gem/Nab did not confer a survival benefit in this group (HR, 0.84; 95% CI, 0.61-1.15; p = 0.27). For patients receiving neoadjuvant Gem/Nab, adjuvant Gem/Nab or other regimens was not associated with improved OS (HR, 0.92; 95% CI, 0.64-1.34; p = 0.69). Conclusions Survival benefits of adjuvant chemotherapy in resected BRPC/LAPC may be regimen-dependent. Postoperative continuation of FOLFIRINOX appeared to be associated with a survival advantage, whereas regimen de-escalation or adjuvant chemotherapy following neoadjuvant Gem/Nab demonstrated no clear benefit.