Guidelines recommend febrile neutropenia (FN) prophylaxis following myelotoxic chemotherapy with either daily injections of filgrastim (Neupogen) or biosimilar filgrastim-sndz (Zarzio/Zarxio), single-injection pegfilgrastim (Neulasta), or pegfilgrastim administered through an on-body injector (PEG-OBI; Neulasta Onpro). PEG-OBI failure rates up to 6.9% have been reported, putting patients at incremental risk for FN and FN-related hospitalization. Our objective was to estimate, from a US payer perspective, the incremental costs of FN hospitalizations and the total incremental costs associated with PEG-OBI prophylaxis at varying device failure rates over assured FN prophylaxis with daily injections of filgrastim or filgrastim-sndz or a single injection of pegfilgrastim. Cost simulations comparing prophylaxis with PEG-OBI at failure rates of 1-10% versus assured prophylaxis in cycle 1 of chemotherapy were performed for panels of 10,000 patients with lung cancer treated with cyclophosphamide, doxorubicin, and etoposide (1 analysis) or non-Hodgkin lymphoma (NHL) treated with CHOP or CNOP (2 analyses). Daily injection scenarios were 4.3, 5, and 11 injections for lung cancer and 5, 6.5, and 11 for NHL. The analyses are from the US payer perspective. For lung cancer, the total incremental cost of PEG-OBI prophylaxis at varying failure rates and durations ranged from $6,691,969‒$31,765,299 over filgrastim and $18,901,969‒$36,538,299 over filgrastim-sndz. For NHL, in scenario 1, the total incremental costs ranged from $6,794,984‒$30,361,345 over filgrastim and $19,004,984‒$35,911,345 over filgrastim-sndz; in scenario 2, the incremental costs ranged from $7,003,657‒$32,448,067 over filgrastim and $19,213,657‒$37,998,067 over filgrastim-sndz. In this simulation, the incremental costs of FN-related hospitalization due to PEG-OBI failure in cycle 1 compared to assured prophylaxis with reference pegfilgrastim, reference filgrastim, and biosimilar filgrastim-sndz varied depending upon the PEG-OBI failure rate and the alternative G-CSF prophylaxis option. Biosimilar filgrastim-sndz offers the greatest cost-efficiency.