INTRODUCTION: The randomized phase III KEYNOTE-522 trial demonstrated that addition of pembrolizumab to neoadjuvant chemotherapy provided a significant improvement in event-free survival and a favorable trend in overall survival for high-risk early-stage triple-negative breast cancer (eTNBC). This analysis evaluated the cost-effectiveness of pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single-agent adjuvant treatment after surgery vs. neoadjuvant chemotherapy for patients with high-risk eTNBC in the USA. METHODS: The analysis was conducted from a US third-party public healthcare payer perspective. A multistate transition model was developed using efficacy and safety data from the KEYNOTE-522 trial. The model included four mutually exclusive health states: event-free, locoregional recurrence, distant metastasis, and death to simulate patients' lifetime disease course. Quality-adjusted life years (QALYs) were calculated on the basis of EuroQoL-5 Dimensions utility data collected in KEYNOTE-522. Costs for drug acquisition/administration, adverse events, disease management, and subsequent therapies were reported (2021 US dollars). Costs and outcomes were discounted at 3% annually. A series of sensitivity analyses were performed to test the robustness of the main results. RESULTS: In the base case scenario, pembrolizumab plus chemotherapy followed by pembrolizumab resulted in expected gains of 3.37 life years (LYs) and 2.90 QALYs, and an incremental cost of $79,046 versus chemotherapy. The incremental cost per QALY gained was $27,285, which is lower than all commonly cited US willingness-to-pay thresholds. Sensitivity analyses showed the results were robust over plausible values of key model inputs and assumptions. CONCLUSIONS: Compared with neoadjuvant chemotherapy, pembrolizumab in combination with chemotherapy as neoadjuvant treatment and continued as a single-agent adjuvant treatment after surgery is considered a cost-effective option for high-risk eTNBC in the USA.