Background: T-DXd is a HER2 antibody–drug conjugate. It improves patient outcomes and is FDA approved for the treatment of patients with Her-2 positive and Her-2 low metastatic breast cancer. However, the impact of T-DXd use in real life compared with the findings reported in clinical trials with strict inclusion criteria has rarely been assessed. We performed a real-world study to evaluate the outcomes of patients with advanced HER2+ and HER2-low expression breast cancer. Methods: We conducted a retrospective single institution study and collected the clinical and pathologic data of patients with metastatic breast cancer who were treated with T-DXd from 2019 to 2022. The primary end point, time to treatment failure (TTF) was defined as the interval from T-DXd initiation to discontinuation. We compared the TTF of T-DXd with previous lines of treatment and also report its safety and tolerability. Results: Thirty-one patients were included in this study, seventeen with HER2-low expression and fourteen with HER2 positive. Patients had received a mean of three prior lines of therapy (ranging from 1 to 13). 32.2% of patients had ≥ 5 lines of therapy prior to T-DXd. TTF was 104 days, 95% CI [58,162] in T-DXd compared with 151 days, 95% CI [119,217] in the previous line of therapy. 2 patients (6.4%) had treatment discontinuation due to adverse events (AEs) (1 patient due to grade 3 fatigue and 1 patient due to concern for ILD). 3 patients (9.6%) had treatment delay or dose reduction due to AEs. A total of 67.7% of patients (21/31) developed AEs on T-DXd. 4 (12.9%) had grade 3 or 4 AEs. Fatigue was the most common AE followed by nausea/vomiting and thrombocytopenia. A total of 17 patients had T-DXd discontinued-15 patients discontinued due to progression or death, 2 discontinued due to AEs. 9 out of 31 patients had brain metastasis. Amongst patients with brain metastases, 7 showed stable disease while on T-DXd (1 had previously progressed on tucatinib, trastuzumab, and capecitabine). In the subgroup analysis, in patients with HER2-low expression, TTF was 98 days 95% CI [41-153] with T-DXd compared with 192 days, 95% CI [84,363] in the previous line of therapy. 2 out of 14 patients developed grade 3 or 4 AEs. Fatigue was the most common AE. In HER2+ subgroups, TTF was 126 days, 95% CI [58,353] in T-DXd vs 125 days, 95% CI [106,217] in the previous line of therapy. 2 out of 17 patients developed grade 3 or 4 AEs. Conclusions: To the best of our knowledge this is the first real life retrospective study evaluating the efficacy and tolerability of T-DXd. Overall, T-DXd had acceptable efficacy and tolerable toxicity in heavily pretreated patients. T-DXd showed a good response rate in patients with active brain metastasis. Our findings are consistent with published data on T-Dxd but is limited by virtue of retrospective series.