1117 Background: A series of retrospective studies have reported a higher incidence of central nervous system (CNS) metastases in HER-2-positive (HER-2+) metastatic breast cancer. Trastuzumab, which does not cross the blood-brain barrier, has been associated with this increased risk. Methods: The aim of this study was to evaluate incidence, survival, and risk factors of CNS metastases in the incident breast cancer population systematically collected by the Tumor Registry of Parma Province over the 4-year period, 2004–2007. Study endpoints were: any distant metastasis as first event; CNS metastasis as first event; CNS metastasis at any time. Associations between CNS metastases and HER-2 status in the entire population and between trastuzumab and CNS metastases in HER-2+ patients (pts) were estimated. A multivariate analysis was performed to test the effect of covariates. Results: We evaluated the total resident population (n = 1500) of breast cancer pts diagnosed during the period 2004–2007 in Parma Province. Two-hundred and twenty-five pts (15%) were HER-2+ (IHC 3+/FISH amplified). Of these, 100 pts were treated with adjuvant trastuzumab-based therapy. At a median follow-up of 36 months from the diagnosis, the incidence of CNS relapse was 3% (1.3% as first recurrence). The median time to death from the diagnosis of CNS metastases was 25 months. Among the HER-2+ pts, there was a significant association between trastuzumab and subsequent CNS metastases (p = 0.02). However, in multivariate analysis, HER-2 status regardless of trastuzumab therapy was found to be the only independent predictive factor for CNS metastases (either as first or as subsequent recurrences; p < 0.01). Conclusions: This is the first population-based registry study analyzing CNS metastases in breast cancer in relation to tumor biological features, systemic treatment, and clinical outcome. Based on our results, HER-2 status independently distinguishes pts with a higher risk of CNS metastases. It is however presumable that, in some cases, improvements in systemic control and overall survival associated with trastuzumab-based therapy lead to an “unmasking” of CNS relapse that would otherwise have remained clinically silent prior to a patient's death. No significant financial relationships to disclose.