Nanoliposomal irinotecan plus 5-fluorouracil/leucovorin (nal-IRI+5-FU/LV) is one of the standard treatments for patients with gemcitabine-refractory metastatic pancreatic ductal adenocarcinoma (PDAC). We have previously reported the real-world clinical data of nal-IRI+5-FU/LV in Japanese patients with PDAC (HGCSG2101). Herein we compared the efficacy and safety of nal-IRI+5-FU/LV by UGT1A1 status, wild type (WT) versus single heterozygous (SH), among the patients enrolled in the HGCSG2101. We retrospectively analyzed patients who received nal-IRI+5-FU/LV for unresectable PDAC at 10 institutions between June and December 2020. Data cutoff for this analysis was 30 June 2021. The median overall survival (OS), progression free survival (PFS) with each 95% confidence interval (CI) were estimated by the Kaplan-Meier method. Differences in the efficacy between each group were tested by means of the Log-rank test. The Cox regression analysis was used to estimate hazard ratios (HRs) of SH compared with WT with 95 % CIs. Tumor response was assessed by RECIST ver. 1.1. Adverse events were evaluated according to CTCAE ver. 5.0. Qualitative and quantitative variables were compared using the chi-square test or Fisher’s test and using a nonparametric (Wilcoxon) test, respectively. A total of 48 patients were evaluated (26 and 22 patients with UGT1A1 WT and SH, respectively). The number of patients who had their initial dose of nal-IRI reduced for any reason was 6 (23.1%) in the WT group and 10 (45.5%) in the SH group, respectively (p=0.20). The median relative dose intensity of nal-IRI was 0.79 (range, 0.43-0.99) in WT group and 0.69 (range, 0.55-0.96) in SH group, respectively (p=0.18). The median PFS was 2.8 months (95%CI: 1.9-6.9) in WT group and 2.4 months (95%CI: 1.9-6.0) in SH group, respectively (HR: 1.2, 95%CI: 0.6–2.1, p=0.63). The median OS was 6.6 months (95%CI: 4.7-11.3) in WT group and 6.8 months (95%CI: 4.3-9.4) in SH group (HR: 1.1, 95% CI: 0.5–2.1, p=0.90), respectively. The response rate was 8.0% (95%CI: 1.7-26.1) in WT group and 16.7% (95%CI: 5.0-40.1) in SH group (p= 0.63), respectively. Though there were no significant differences in safety between WT and SH groups, ≥grade3 neutropenia and febrile neutropenia were observed more frequently in SH group (≥grade3 neutropenia: 30.8% vs 50.0%, p=0.24, febrile neutropenia: 0.0% vs 9.1%, p=0.20, respectively). No treatment-related death was observed in each group. There was no significant difference in the treatment outcome of nal-IRI+5-FU/LV between UGT1A1 WT and SH groups. However, ≥grade3 neutropenia and febrile neutropenia tended to be more frequent in SH group despite the fact that more patients had reduced the initial dose of nal-IRI in SH group. Further analysis is needed to investigate the impact of the UGT1A1 status on the treatment outcome of nal-IRI+5-FU/LV for patients with PDAC.