OBJECTIVES: T-DM1, an antibody-drug conjugate which combines the antitumor properties of trastuzumab (H) with the cytotoxic agent DM1, is approved for the treatment of patients with MBC previously treated with trastuzumab+taxane.  We compared the clinical effectiveness of T-DM1 versus all available therapies used in the treatment of unresectable HER2-positive locally advanced breast cancer (LABC) or MBC. METHODS: This systematic review (SR) and indirect treatment comparison (ITC) included all published data between January 1, 1998 and December 20, 2012. Studies were chosen in accordance with conventional methods for performing and reporting SRs and ITCs (i.e., Cochrane Handbook for SRs, PRISMA, ISPOR guidelines, and major HTA agencies). Eligible trials were controlled trials of treatments for unresectable HER2-positive LABC or MBC that had progressed after treatment with combination of trastuzumab+taxane in the adjuvant or MBC setting. Progression had to have occurred after the most recent treatment for LABC or MBC or within 6 months after treatment for early-stage disease.  RESULTS: Seven RCTs and two non-randomized controlled trials (n-RCTs) met the inclusion criteria. Of the seven RCTs, five had a common comparator, being eligible for the ITC. The other two RCTs and two n-RCTs did not have a common comparator and were thus not included in the ITC. T-DM1 was the only treatment to demonstrate statistically significantly longer overall survival (OS) and progression-free survival (PFS) when directly compared to capecitabine+lapatinib, and when indirectly compared to capecitabine+trastuzumab (PFS HR [95% CI]: 0.53 [0.32, 0.86], p=0.01; OS HR [95% CI]: 0.56 [0.35, 0.91]; p=0.01) and capecitabine monotherapy (PFS HR [95% CI]: 0.36 [0.25, 0.51]; p<0.0001); OS (HR [95% CI]: 0.53 (0.39, 0.72); p=0.0009).  CONCLUSIONS: In this ITC, T-DM1 was associated with longer OS and PFS versus capecitabine+trastuzumab and capecitabine monotherapy in patients with HER2-positive LABC or MBC with disease progression after treatment with trastuzumab+taxane.