Introduction: Weekly administration of nanoparticle albumin-bound (nab) paclitaxel as a first-line treatment for metastatic breast cancer (MBC) has not been fully investigated. The addition of trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is less understood. This phase II study evaluated the efficacy and safety of weekly nab paclitaxel in the first-line MBC setting. Patients whose tumors overexpressed HER2 also received trastuzumab.Patients And Methods: Patients with locally advanced or metastatic breast cancer received nab paclitaxel (125 mg/m(2)) by 30-minute intravenous infusion weekly for 3 of 4 weeks. Patients who were HER2-positive received concurrent trastuzumab.Results: Seventy-two patients were enrolled; HER2 expression was detected in 22 patients. The overall response rate (ORR) was 42.2% (95% CI, 30%-55%); 5 patients had a complete response (CR) and 22 patients had a partial response (PR). Additionally, 17 patients experienced stable disease (SD), providing an overall benefit (CR + PR + SD) of 68.8%. Patients with HER2-positive tumors had an ORR of 52.4%; the ORR was 38.1% in the HER2-negative population (P = .3). Median progression-free survival was 14.5 months (range, 1-49.3 months) and survival rates at 1 year and 2 years were 69% and 62%, respectively. The most commonly observed toxicities were pain (64%), fatigue (58%), sensory neuropathy (54%), infection (46%), nausea (38%), alopecia (33%), and anemia (33%).Conclusion: Our findings demonstrate that weekly nab paclitaxel has a favorable safety profile and is well tolerated as a first-line treatment for MBC. An ORR of 42% and an overall benefit of 69% is extremely encouraging, particularly in the HER2-positive population where 52% of patients responded.