Background: The Oncology Care Model (OCM), a 6-year long Medicare value-based care program, rewards practices for decreasing total cost of care (TCOC) compared to a benchmark price, while maintaining high quality cancer care. Care services for enrolled patients are divided into 6-month episodes within 1-year time intervals called Performance Periods (PP). One approach to reducing TCOC is reducing the expenditure for drug waste. In mid-2017, trastuzumab (HER2-targeted monoclonal antibody) 420 mg multi-dose vial (MDV) was discontinued and replaced with a 150 mg single-dose vial (SDV), leading to wastage of the remaining partial quantities of the SDV after preparation of a patient-defined dose. The increased drug waste led to an increase in the total drug cost of trastuzumab and TCOC. Late 2019, MDV and SDV biosimilar trastuzumab products were introduced, and The US Oncology Network (The Network) practices adopted the MDV biosimilar as a strategy to reduce drug waste and TCOC. This study highlights the impact of trastuzumab drug waste on TCOC. Methods: Claims data for 14 Network practices, participating in OCM, were assessed. The financial impact of drug waste and TCOC for The Network’s transition from MDV trastuzumab to SDV trastuzumab in 2017, and from SDV trastuzumab to the MDV biosimilar trastuzumab in 2020 was evaluated. Results: With the use of MDV trastuzumab during OCM PP1, drug waste accounted for 0.05% of the total dose of trastuzumab. After having to shift from MDV to SDV during PP2, as a result of the packaging change, trastuzumab drug waste increased to 10.25% of the total dose, with an increase in TCOC by 0.25% ($2M) per PP during PPs 3-7. As The Network practices adopted the use of MDV biosimilar trastuzumab starting in PP8, drug waste declined 57% to 4.4% of the total dose in PP9, reducing the drug waste component of TCOC by $1.4M (0.16%). Had all SDV trastuzumab doses been transitioned to the MDV biosimilar, an additional $600K (0.09%) in TCOC could have been reduced in PP9. Conclusions: TCOC fluctuations can be driven by not just increasing costs or increased utilization, but also by drug packaging and increasing drug waste. The discontinuation of MDV trastuzumab resulted in a substantial financial impact on drug waste, TCOC, and cost for patients. Swift transition to biosimilar MDV trastuzumab within The Network helped to significantly reduce drug waste and its impact on TCOC in the OCM. Trastuzumab biosimilars, in addition to being cost-effective alternatives to biological therapeutics, offer significant cost savings via drug waste reduction.