The purpose of this prospective, nonrandomized, controlled study was to compare the regimen of continuously administering trastuzumab and capecitabine (HX) with the regimen of lapatinib plus capecitabine (LX) for metastatic breast cancer (MBC) patients who are resistant to trastuzumab and have previously received taxane treatment. The patients in the HX group received trastuzumab (6 mg/kg every 21 days following a loading dose of 8 mg/kg on cycle 1) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The patients in the LX group received lapatinib (1,250 mg/day) and capecitabine (2,000 mg/m(2)/day, days 1 to 14 every 21 days). The median progression-free survival (PFS) of the patients in the HX and LX groups was 4.5 vs. 6.0 months, respectively (p = 0.006). The proportion of patients having a PFS ≥ 6 months in the HX and LX groups was 30 vs. 55 %, respectively (p = 0.005). The incidence rate of new brain metastases during treatment was 12 and 3 % in the HX and LX groups, respectively, which was not significantly different (p = 0.16). In conclusion, application of the lapatinib plus capecitabine regimen in MBC patients with a trastuzumab-resistant tumor can more effectively control the disease compared with continuous administration of trastuzumab plus capecitabine.