OBJECTIVES To develop two separate cost-effectiveness analyses, evaluating costs and outcomes of lapatinib associated to capecitabine (LAP/CAP) versus capecitabine alone (CAP) or trastuzumab associated to capecitabine (TRAST/CAP) versus capecitabine alone in the treatment of HER2 positive, metastatic breast cancer patients, previously treated with trastuzumab, under the Brazilian private health care system perspective. METHODS In the absence of a trial comparing directly treatments with LAP/CAP versus TRAST/CAP, two separate studies were identified, each evaluating the efficacy of the combination treatment versus capecitabine alone. Population severity and dosage of capecitabine in the combined arm differed between trials, so an indirect comparison was not possible. Therefore, two independent cost-effectiveness analyses were developed. Only direct medical costs were considered, including medications, follow-up, disease progression and treatment of adverse events. Outcomes were expressed as time-to-progression (TTP). Maximum Prices to Consumer were considered for drug costs and procedure costs were obtained from published tariffs. RESULTS In one year, the analysis comparing LAP/CAP to CAP resulted in 7.01 progression free months for LAP/CAP and 5.74 to CAP. Average costs were BRL130,908 for LAP/CAP and BRL62.960 for CAP, resulting in an ICER of BRL53,484 per additional month without progression. In the same time horizon, the analysis comparing TRAST/CAP to CAP resulted in 7.86 progression free months for TRAST/CAP and 6.64 to CAP. Average costs were BRL179.522 for TRAST/CAP and BRL70,012 for CAP, resulting in an ICER of BRL89,852 (USD64,180) per additional month without progression. (2005 PPP index 1USD=1.4BRL) CONCLUSIONS Associating lapatinib to treatment with capecitabine leads to gains in time-to -progression of 1.27 months, with an average cost per additional month without progression of BRL53,484. In similar conditions, although evaluated in a different population, trastuzumab associated to capecitabine leads to 1.22 month gains in TTP with an average cost per additional month without progression of BRL89,852.