Background: Until 2020, in human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), the two first lines of metastatic treatment were well defined but after, many options were possible, most often combining targeted therapy plus chemotherapy. Eribulin mesylate is indicated for the treatment of patients with ABC previously treated by anthracycline and taxane regimens in the advanced setting. Here, we present the results of eribuline and trastuzumab (E/T) combination in HER2-positive ABC previously treated. Methods: Patients with HER2-positive ABC treated with the E/T combination from our region cancer institute were included in this retrospective study. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR) and safety. Results: Between November 2013 and July 2019, a total of 34 consecutive patients with HER2-positive ABC were included. The median number of previous lines for advanced setting was 4 (range 2-7). Patients treated by taxanes and anthracyclines represented 91% and 47% respectively; 50%, 79% and 62% were previously treated with pertuzumab, trastuzumab emtansine and lapatinib respectively. After a median follow up of 24.8 months, median PFS was 6.2 months (95% CI [3.35-7.13]) and median OS was 12.6 months (95% CI [7.13-18.56]). The ORR and CBR were 38% and 53%, respectively. No unexpected adverse event was observed. The most frequent grade 3-4 toxicity was hematologic (44.1%). Conclusions: Recently, new therapies have revolutionized the management of HER2-positive ABC and patients benefit from a prolonged overall survival associated with a maintained performance status. However, in pretreated and advanced metastatic setting, there are few scientific evidence to guide the choice of treatments. A combination of E/T could be an effective option in patients with good performance status and willing to receive treatment.