Background: To evaluate efficacy in patients with brain metastasis (BM) on entry into the lapatinib expanded access program (LEAP).Methods: LEAP is a worldwide, single-arm, open-label study. HER2-positive, locally-advanced or metastatic breast cancer patients with progression after an anthracycline, taxane, and trastuzumab were eligible. Patients received capecitabine 2000 mg/m2 daily in two divided doses, days 1-14, every 21 days and lapatinib 1250 mg once daily.Results: Among 186 patients enrolled in 6 Korean centers, 58 had BM. Progression-free survival (PFS) was 18.7 weeks in patients with BM and 19.4 weeks without BM (P = 0.88). In patients with BM, brain response was synchronized with systemic responses (P = 0.0001). Overall survival (OS) was 48.9 weeks in patients with BM and 64.6 weeks without BM (P = 0.23). Multivariable analysis found hormone receptor positivity (P = 0.003) and clinical benefit rate (CBR) of combined systemic and brain disease (P < 0.0001) significantly associated with prolonged brain PFS, and CBR of combined systemic and brain disease (P = 0.03) and longer trastuzumab use (P = 0.047) associated with prolonged OS in patients with BM; prior capecitabine did not affect PFS or OS in patients with BM.Conclusion: Lapatinib plus capecitabine is equally effective in patients with or without BM.Trial registration: ClinicalTrials.gov (NCT00338247). © 2012 Ro et al.; licensee BioMed Central Ltd.