Background: FFX and GnP are the most common 1L treatments for mPDAC. Each regimen is associated with a different profile of toxic effects that impact quality of life. However, the regimens have not been directly compared for safety or efficacy in a randomized controlled trial. RW studies of the frequency of adverse events (AEs) under each regimen have reported inconsistent results. Supportive care such as granulocyte colony-stimulating factor (G-CSF) also affects the rate of hematologic AEs. We assessed AEs and G-CSF use in a RW cohort of mPDAC pts treated with FFX or GnP in the 1L. Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between November 2018 and November 2022 who initiated treatment with 1L FFX or GnP within 90 days of their diagnosis for metastatic disease were included in the study. Diarrhea, fatigue, nausea and vomiting, and neuropathy were available in the data as ungraded AEs abstracted from clinician notes. Assessment of hematologic and hepatic AEs were based on observed lab values and were graded according to the Common Terminology Criteria for AEs version 5. Results: 2,918 pts met study inclusion criteria: 1,703 received 1L GnP and 1,215 received 1L FFX. For the GnP vs. FFX cohorts, the median age at 1L initiation was 71yr (IQR: 64–76) vs. 65yr (IQR: 58–71), 52% vs. 57% were male, 65% vs. 68% were white, 9% vs. 15% had an ECOG score of 0, and 40% vs. 39% had an ECOG score of 1. GnP pts had a statistically significantly greater rate of grade 1/2 and 3/4 neutropenia (26% vs. 15%, p = .001; 25% vs. 17%, p = .014), grade 1/2 thrombocytopenia (25% vs. 20%, p < .001), grade 1/2 and 3/4 anemia (87% vs. 68%, p < .001; 19% vs. 6%, p = .001), grade 1/2 elevated ALT (62% vs. 44%, p < .001), grade 1/2 elevated AST (68% vs. 50%, p < .001), and grade 1/2 elevated ALP (68% vs. 58%, p < .001). For GnP vs. FFX, there was no statistically significant difference in grade 3/4 thrombocytopenia (9% vs. 5%, p < .001), grade 3/4 elevated ALT (6% vs. 5%, p = .367), grade 3/4 elevated AST (9% vs. 5%, p = .170), grade 3/4 elevated ALP (11% vs. 11%, p = .417), and grade 1/2 and 3/4 hypokalemia (32% vs. 34%, p = .241; 7% vs. 13%, p = .060). There were not statistically significant differences for GnP vs. FFX for AEs reported in clinician notes including diarrhea (12% vs. 18%, p = .074), fatigue (15% vs. 12%, p = .187), nausea and vomiting (10% vs. 11%, p = .399), and neuropathy (15% vs. 12%, p = .219). G-CSF was used by 19% vs. 57% of GnP vs. FFX patients (p < .001), with median time to first use of G-CSF 14 days (IQR: 7–35) vs. 0 days (IQR: 0–14). Conclusions: In a RW cohort of mPDAC pts treated with 1L GnP or FFX, pts experienced a variety of serious AEs. The burden of AEs was higher among the RW GnP cohort than the RW FFX cohort. G-CSF was more prevalent and began earlier in the FFX cohort, indicating prophylactic use.