1125 Background: A significant improvement in overall survival was observed in the last two decades in patients with breast cancer due to early diagnosis and more effective therapies. However, a significant improvement in metastatic setting has been questioned. Our population based study was aimed to investigate the outcome of metastatic breast cancer from 1988 to 2005. Methods: Women with stage IV de novo or relapsed breast cancer diagnosed between 1988 and 2005 were identified by the Modena Cancer Registry (MCR). For all patients overall survival (OS) was measured from the date of first distant metastases to the date of death from any cause or last follow-up and compared across groups for four periods of similar duration time: 1988–1993 (A), 1994–1997(B), 1998–2001(C), 2002–2005(D). Results: Among 8,654 patients with breast cancer identified by the MCR, 409 had an initial metastatic disease (4.8%) and 693 (8.4%) had a distant recurrence. Median age at onset was 66 versus 59 years in de novo vs relapsed disease (p = 0.001). Significant differences for postmenopausal age (80% vs 71%) and for positive estrogen receptors (72% vs 63%) were registered in de novo and relapsed disease, respectively (p = 0.001). After a 27 months median follow-up for initial metastatic disease, the five-year OS was 12%, 14%, 9%, and 13% in the A, B, C, and D periods, respectively, (p = 0.5). Conversely, in relapsed breast cancer, after a 29 months median follow-up, a significant survival improvement was observed between the first and the other three periods, being the 5 year-survival rate after recurrence 10%, 22%, 30%, and 25%, respectively (p = 0.001). A survival improvement was seen in the last ten years for relapsed breast cancer using aromatase inhibitors (p < 0.0001) while for initial metastatic disease the same treatment provided a better outcome only in the last 4 years (p < 0.0001). Conclusions: Data from our study show that the outcome of initial metastatic breast cancer is still discouraging, despite the availability of several new drugs in recent years. A limited improvement was observed in relapsed breast cancer with the aromatase inhibitors introduction. In any case, the finish line is still far away, and robust investments in basic and translational research are still absolutely necessary. No significant financial relationships to disclose.