Abstract Background. A higher incidence of central nervous system (CNS) metastases in HER-2–positive metastatic breast cancer (MBC) has recently been reported. Materials and Methods. Aims of this observational study were to evaluate the incidence of CNS metastases in HER-2–positive MBC patients, to define the outcome of patients with CNS metastases, and to identify the risk factors for CNS relapse. Results. Between April 1999 and June 2005 we treated 122 consecutive HER-2–positive MBC patients with chemotherapy and trastuzumab. At a median follow-up of 28 months from the occurrence of metastatic disease, 43 patients (35.2%) developed CNS metastases. The median time to death from the diagnosis of CNS metastases was 23.46 months. At multivariate analysis we found that only premenopausal status at diagnosis of breast cancer and visceral metastases as the dominant site at relapse were significantly associated with a higher risk for CNS metastases. Conclusion. The CNS metastasis incidence is very high in HER-2–positive MBC, but the survival after CNS relapse in these patients is longer than in patients unselected for HER-2 status, because of the better control of extracranial disease obtained by trastuzumab. The identified risk factors for CNS relapse could allow us to select a subgroup of HER-2–positive MBC patients as candidates for active surveillance for CNS progression (by computed tomography or magnetic resonance imaging) and/or as candidates for accrual in trials of prevention of CNS relapse.