Background: An oral fluoropyrimidine, S-1, is a standard adjuvant (adj) chemotherapy practice in Japan for patients (pts) with resected pancreatic cancer (PC). Patients experiencing recurrence after adj S-1 administration are treated with FOLFIRINOX (FFX), including intravenous fluoropyrimidine, or gemcitabine plus nab-paclitaxel (GN), which is commonly used as the first-line chemotherapy approach in pts with advanced PC. Some pts have good response to FFX with acceptable toxicity levels even though recurrence within 6 months (mo) after the last S-1 administration is attributed to PC refractory to fluoropyrimidine. To the best of our knowledge, there is no clinical study comparing FFX and GN in this particular population. Methods: This multi-center, retrospective study included pts with PC that had a recurrence-free interval (RFI) < 6 mo from the last adj S-1 administration and were treated with FFX or GN between December 2013 and 2018. The decision to administer FFX or GN was taken by the attending physicians. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response, and serious adverse events (SAE). The OS and PFS were calculated from the time of initiation of treatment with FFX or GN. To adjust confounding factors in the comparison of FFX with GN, propensity score-matching (PSM) analysis was performed. Potentially confounding factors were identified by univariate analysis for OS, and statistical significance was set at p < 0.1. Results: A total of 284 (FFX; 50, GN; 234) pts were enrolled from 32 institutions in Japan. Potential confounding factors comprised curability, pathological T/N, tumor differentiation status, reasons for the end of S-1 administration, chemotherapy regimen, performance status, serum albumin/C-reactive protein/carbohydrate antigen 19-9 levels, and presence or absence of liver metastasis before initiating the administration of FFX or GN. After PSM, 43 pts each in the FFX and GN groups were compared in pairs. The patient characteristics, excluding age, in the matched pair were well-balanced; the proportion of pts aged < 65 years in the FFX and GN groups was 61% and 30%, respectively. The median OS and PFS were longer in the GN group than in the FFX group; OS was 14.5 vs. 11.1 mo (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.38-0.97); PFS was 7.1 vs. 5.1 mo (HR, 0.65; 95% CI, 0.41-1.02). The objective response, disease control rates, and observed SAE in the GN and FFX groups were 20/19%, 80/66%, and 14/19% respectively. Seventy-two percent of the pts in the GN group received subsequent therapies of FFX/S-1/FOLFIRI/FOLFOX (28/12/9/5%); while 77% of the FFX group pts received subsequent therapies of GN/GEM (54/7%). Conclusions: Real world data suggests that GN may be recommended in PC pts with RFI < 6 mo from the last administration of adj S-1.