Data regarding the use of rechallenge trastuzumab (RTmab)-based therapies in the management of heavily pretreated patients with HER2-positive breast cancer (BC) in the literature are limited. This study aimed to evaluate the efficacy of trastuzumab-based therapy in patients who experienced disease progression after receiving lapatinib plus capecitabine (LC). In this retrospective study, the data of thirty three HER2 positive metastatic BC patients who progressed after LC treatment and subsequently received trastuzumab-based treatment were evaluated. Trastuzumab was administered at an initial loading dose of 8 mg/kg followed by a maintenance dose of 6 mg/kg every 21 days. The average age of patients is 47 years (range 25-72 years). The predominant histopathological subtype was invasive ductal carcinoma, which was observed in 23 (70%) patients. Estrogen receptor (ER) positivity was also noted in 16 (48%) patients. All patients had received palliative trastuzumab plus chemotherapy (Cht) before the lapatinib. In conjunction with trastuzumab-based therapy, vinorelbine was administered to 14 (42%) patients, paclitaxel to 12 (36%), and other chemotherapeutic agents to 4 (12%). For all patients, the objective response and disease control rates were 27% and 69%, respectively. Furthermore, the median progression-free survival (PFS) was 8.8 months (95% confidence interval [CI]: 6.6-11), and the median overall survival was 20 months (95% CI: 15.1-25.8). There were no statistically significant differences in PFS rates based on several factors, including age, ER status, denovo metastasis, brain metastasis, perioperative Cht, pre-Rtmab hormone therapy, and which Cht was used along with Rtmab (P > .05). Mild to moderate adverse events were observed in 17 (52%) patients, whereas only 4 (12%) patients had Grade 3 to 4 toxicity. This study demonstrated that RTmab-based therapy is effective in patients who progressed after LC. These findings contribute to the literature by suggesting that RTmab is a viable treatment option for patients with HER2-positive metastatic BC.