BACKGROUND: This study aims to evaluate the cost-effectiveness of Trastuzumab deruxtecan (T-DXd), compared to trastuzumab emtansine (T-DM1) as second-line treatments for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) patients in Iran. METHODS: A partitioned survival model was developed based on time-to-event data from the DESTINY-Breast 03 trial to evaluate the cost-effectiveness of T-DXd versus T-DM1 from a societal perspective and over a lifetime horizon. Costs and utility inputs were derived from published literature and official Iranian sources. Key outcomes included total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICER). The willingness-to-pay (WTP) threshold of $2413/QALY was applied. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were conducted to assess uncertainty. RESULTS: In the base-case analysis, T-DXd yielded 3.59 QALYs for $261,315, while T-DM1 yielded 1.89 QALYs at $258,039, resulting in an ICER of $1,927 per QALY. This value is below Iran's WTP threshold of $2413/QALY. One-way sensitivity analysis identified the unit price of T-DXd as the most influential parameter. PSA results indicated that T-DXd has a 52% probability of being cost-effective. CONCLUSION: T-DXd represents a cost-effective alternative to T-DM1 as a second-line treatment for HER2-positive MBC in Iran. Its clinical advantages, combined with an ICER below the local WTP threshold, support its adoption in this patient population.