The global phase 3 NAPOLI -1 trial of patients with pancreatic ductal adenocarcinoma (PDAC) demonstrated an overall survival (OS) benefit from using liposomal irinotecan and 5-fluorouracil/leucovorin (nal-IRI + 5-FU/LV) after treatment with gemcitabine (GEM) compared to 5-FU/LV alone. However, the efficacy and safety of this regimen in older patients are not well studied. We conducted a single-center retrospective study to compare the therapeutic efficacy of nal-IRI + 5-FU/LV between older and younger patients with cutoff ages of 70 and 75years, respectively. We included patients with a prior history of one or more GEM-based regimens for locally advanced or metastatic PDAC and were treated with nal-IRI + 5-FU/LV. Of the 115 patients, 54 (47.0%) and 24 (20.9%) were aged ≥ 70 and ≥ 75years, respectively. The median OS and progression-free survival (PFS) of the entire cohort were 8.5 and 3.6months, respectively. No significant differences were observed in OS and PFS hazard ratios using age cutoffs of 70 (P = 0.90 and 0.99, respectively) and 75 (P = 0.90 and 0.76, respectively) years. Additionally, no significant differences were found in the incidence of treatment-related adverse events (trAEs) between patients aged ≥ 70 and < 70years or those aged ≥ 75 and < 75years. Other than hematological toxicity, no trAEs higher than Grade 4 were observed in either age group. The efficacy and safety of nal-IRI + 5-FU/LV for patients with PDAC are not significantly different for those aged ≥ 70years compared to younger patients.