Background: Modifications to the FOLFIRINOX (FFX) regimen are used in the real world to attempt to decrease side effects and increase tolerability for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). This study assesses patterns in real-world modifications to first-line (1L) FFX and total cost of care per administration cycle in the Medicare Fee-For-Service (FFS) population. Methods: We used ICD-10 diagnosis codes to identify patients aged 65+ with mPDAC without end-stage renal disease in the 2018-2021 Medicare Parts A, B, and D 100% Research Identifiable Files (RIF) data. Study patients had 2+ claims with a pancreatic cancer diagnosis and at least one diagnosis of a metastasis anytime on or after the first pancreatic cancer diagnosis. Total cost of care (TCOC) represents mean Medicare paid amounts and patient cost sharing. 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. Study patients were assigned to cohorts based on drugs present within a 48-hour (2-day) period of a 1L FFX chemo infusion cycle: FFX with all 4 component drugs (oxaliplatin, irinotecan, leucovorin, 5-Fluorouracil (5-FU) bolus and infusion), FFX with no 5-FU bolus but with 5-FU infusion, FFX with a 5-FU bolus but no 5-FU infusion, FFX with no 5-FU of any kind, and FFX with no leucovorin. Results: We found 45,755 administrations of 1L FFX regimens across 8,889 patients with mPDAC between 2018 and 2021. Among 1L FFX regimens, the largest cohort was comprised of administrations involving a 5-FU infusion but no 5-FU bolus (21,619 administrations, or 47%). The second largest cohort received all 4 FFX component drugs (15,565 administrations, or 34%). The other cohorts were patients receiving FFX with no leucovorin (6,300 administrations, or 14%), FFX with a 5-FU bolus but no infusion (1,425 administrations, or 3%) and patients receiving FFX with no 5-FU of any kind (842 administrations, or 2%). Administrations containing all 4 drug components had the highest cost per cycle ($7,515), and those with no 5-FU of any kind had the lowest ($6,715). Conclusions: Among Medicare beneficiaries receiving 1L FOLFIRINOX (FFX) regimens to treat mPDAC, only 34% of administrations of FFX contained all four components. Administrations most frequently omitted the 5-FU bolus. Administrations containing all 4 drug components had higher costs per cycle and those with no 5-FU of any kind had the lowest cost per cycle.