Background: Nanoliposomal irinotecan (NAL-IRI) and fluorouracil with folinic acid (NFF) is the standard regimen after gemcitabine-based therapy for unresectable or recurrent pancreatic cancer (urPC). We conducted this NAPOLEON-2 study to investigate the efficacy and safety of NFF and explore the predictive or prognostic factors, retrospectively and prospectively, in the real world. We previously reported the interim analysis of the retrospective data 6 months after the end of data collection (Ann Oncol. 2022;33(suppl 4): S289-S290). Here, we report the final data 1 year after data collection. Methods: We retrospectively collected data from urPC patients treated with NFF who received at least one previous chemotherapy in 21 hospitals in Japan from June 2020 to May 2021. Patient characteristics, treatment efficacy, and adverse events were analyzed. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan–Meier analysis. OS and PFS among the therapeutic lines of NFF were also analyzed. Results: NFF was administered to 161 patients. The median follow-up period was 7.3 months (95% confidence interval [CI], 5.6–8.9); median age, 67 years (range, 38–85), with 73 female patients (45%). The Eastern Cooperative Oncology Group performance status was 0/1/2/3 in 74/76/10/1 patients, respectively. Nineteen patients (12%) had locally advanced disease; 142 (88%) had metastatic disease; 89 (55%) had liver metastasis; and 44 (27%) had peritoneal metastasis. All patients previously received gemcitabine-based therapy. NFF was administered as 2nd/3rd/4th-or-later-line therapy to 104/41/16 patients, respectively. The median OS was 8.1 months (95% CI, 7.1–9.7); median PFS, 3.4 months (95% CI, 2.8–4.4); overall response rate, 5%; and disease control rate, 52%. The relative dose intensity was 81.6% with NAL-IRI and 90.7% with fluorouracil. The initial dose of NAL-IRI was reduced in 57 patients (35%), mainly owing to UGT1A1 examination status (8%), followed by decreased organ function or worsened performance status (6%). Dosage reduction during treatment (independent of the initial dose reduction) was performed in 67 patients (42%), mainly owing to neutropenia (16%) and anorexia (11%). Frequent Grade 3/4 adverse events were neutropenia (24%), anorexia (12%), and leukopenia (12%). No Grade 5 adverse events were observed. The median OS and PFS for NFF in the 2nd-line group, compared with the 3rd-or-later-line group, were 7.6 vs 9.1 months (hazard ratio [HR], 0.92; 95% CI, 0.64–1.35; p = 0.68) and 2.9 vs 3.8 months (HR, 0.89; 95% CI, 0.64–1.24; p = 0.49), respectively. Conclusions: NFF had appropriate efficacy and manageable toxicity profiles, consistent with our previous report. NFF could be a candidate for 2nd-or-later-line regimens in the real world.