Background: Pancreatic enzyme replacement therapy (PERT) can reduce symptoms of indigestion and improve nutrition in patients with exocrine pancreatic insufficiency. PERT is under-prescribed, and this may be related to actual costs and prescriber sensitivity to these costs. Thus, we aimed to assess PERT costs. Methods: We used Medicare Part D formulary and pricing files for the first quarter of 2020 to conduct a patient-level modeling study to describe point-of-sale and out-of-pocket costs for each PERT formulation among Part D stand-alone and Medicare Advantage prescription drug plans. We calculated costs across nationwide plans under three scenarios: (1) standard benefit design ($435 deductible and 25% coinsurance after the deductible is met); (2) 25% coinsurance (for fills after the deductible and in the coverage gap until the patient spends $6,350 out-of-pocket); and (3) 5% coinsurance (once catastrophic coverage is reached). PERT doses are identified by the lipase content per capsule (in United States Pharmacopeia, USP, units). We calculated the number of units for each PERT formulation/ dose form that would provide optimally dosed PERT for the average US adult (250,000 USP units of lipase per day), based on guidelines and consensus. We first calculated costs for a single unit of PERT. Next, we calculated the number of units needed daily for each formulation/ dose form to provide optimally dosed PERT, and multiplied it by 30 to generate 30-day requirements and costs. Results: Across 3,974 plans nationwide, five PERT formulations in seventeen different doses were covered by Medicare plans in 2020. The range of lipase content in a single unit ranged from 3,000 to 40,000 USP units, and the per-unit list price ranged from $1.44 to $13.89. The point-of-sale price for a 30-day supply of optimally dosed PERT ranged from $2,109 to $4,840. For patients, the expected out-of-pocket costs for a 30-day supply of optimally dosed PERT averaged $999 across formulations (range, $853 to $1536) for those paying a deductible and coinsurance, $673 (range, $527 to $1210) for fills made after meeting the deductible until reaching catastrophic coverage, and $135 (range, $105 to $242) after reaching catastrophic coverage. Conclusions: In this analysis of 2020 Medicare Part D plans, the estimated out-of-pocket cost for just a 30-day supply of optimally dosed PERT was high— at least $100 in the catastrophic phase and approximately $1,000 in the initial phase. In the setting of pancreas cancer, already associated with heavy symptom burden and distress, the financial burden from a supportive care intervention (such as PERT) has been underappreciated. These costs may serve as a barrier to Medicare beneficiary drug access and contribute to financial toxicity.