Background: FOLFIRINOX (FFX) is often associated with side effects and toxicity. This study examines real-world incidence of adverse events (AEs) and associated costs among Medicare fee-for-service (FFS) beneficiaries with metastatic pancreatic ductal adenocarcinoma (mPDAC) receiving first-line (1L) FFX. Methods: We identified patients aged 65+ with a record indicating a diagnosis of mPDAC between 2018-2021 in the Medicare Parts A, B, and D 100% Research Identifiable Files (RIF) data. Patients were required to have at least two malignant neoplasm of pancreatic duct diagnosis codes on different dates AND at least one diagnosis of a metastasis anytime on or after the first pancreatic cancer diagnosis. Patients with end-stage renal disease were excluded. Patients were assigned to cohorts based on drugs present within a 48-hour (2-day) period of a FFX chemo infusion cycle: 1) FFX with all 4 component drugs (oxaliplatin, irinotecan, leucovorin, 5-FU bolus and infusion), 2) FFX with no 5-FU bolus, but with 5-FU infusion, 3) FFX with a 5-FU bolus, but no 5-FU infusion, 4) FFX with no 5-FU of any kind and, 5) FFX with no leucovorin. Lines of therapy (LOTs) were assigned based on therapies used. LOTs ended the day before a new chemotherapy began, 28 days after the last chemotherapy (if no new chemotherapy), or upon death. Incidence rates of adverse events per administration for each cohort were determined along with the total costs of care and growth factor spending per administration. Results: We identified a total of 45,755 administrations of 1L FFX. Administrations of FFX without 5-FU of any kind (N = 842 administrations) had the lowest incidence of AEs (nausea 21.4%, neutropenia 12.5%, anemia 11.4%, fatigue 9.7%, diarrhea 10.1%, and neuropathy 5.9%), total cost of care ($6,715), and growth factor spending ($792). Administrations with all four FFX component drugs (N = 15,565 administrations) had the highest incidence of neutropenia (27.5%) and fatigue (17.5%) as well as the highest total cost of care ($7,515) and growth factor spending ($1,761). Conclusions: Among patients receiving 1L FFX, administrations with all four component drugs were associated with the highest incidence of adverse events as well as the highest total cost of care per administration cycle. In particular, neutropenia was seen in over twice as many administration cycles in patients receiving FFX with all four components (27.5%) compared to those receiving FFX with no 5-FU of any kind (12.5%). A higher incidence of neutropenia contributes to higher growth factor utilization and therefore higher costs.