Background Novel targeted agents and combinations have become available in multiple lines of treatment for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC). In this context, alternatives to the lapatinib (L) and capecitabine (C) regimen, evaluating L combined with other cytotoxic drugs, are warranted. Patients and Methods In the present phase II, multicenter study, patients with HER2+ MBC with progression after taxane were randomized between L, 1250 mg, combined with C, 2000 mg/m2 on days 1 to 14 (LC), vinorelbine (V), 25 mg/m2 on days 1 and 8 (LV), or gemcitabine (G), 1000 mg/m2 on days 1 and 8 (LG), every 21 days. The primary endpoint was the overall response rate. Results A total of 142 patients were included from 2009 to 2012. No differences were found in the patient baseline characteristics. The median age was 51 years, 69% were postmenopausal, 32% had liver metastasis, 57% were hormone receptor negative, and 48% had been previously treated with trastuzumab. The overall response rate was 49% (95% confidence interval [CI], 34.8%-63.4%), 56% (95% CI, 40%-70.4%), and 41% (95% CI, 27%-56.8%) in the LC, LV, and LG groups, respectively. The median progression-free survival was 9 months in the LC arm and 7 months in the other 2 arms (P =.28). The most common grade 3 and 4 adverse events were hand-foot syndrome (18%), diarrhea (6%), and increased alanine aminotransferase/aspartate aminotransferase (4%) in the LC arm; neutropenia (36%), diarrhea (9%), and febrile neutropenia (6%) in the LV arm; and neutropenia (47%), alanine aminotransferase/aspartate aminotransferase (13%), and rash (4%) in the LG arm. Conclusion LV and LG seem to be active combinations in patients with HER2+ MBC after taxane failure. The overall toxicity was manageable in all regimens.