Abstract: Conventional tumor markers have limited value for prognostication and treatment monitoring in metastatic breast cancer (MBC) patients and novel circulating tumor markers therefore need to be explored. Hyaluronic acid (HA) is a major macropolysaccharide in the extracellular matrix and is reported to be associated with tumor progression. In our study, we investigated plasma HA level with respect to progression free survival (PFS) and overall survival (OS), as well as the treatment monitoring value in MBC patients. The prognostic value of plasma HA level was investigated in a discovery cohort of 212 MBC patients with 2.5-year follow-up and validated in an independent validation cohort of 334 patients with 5-year follow-up. The treatment monitoring value of plasma HA level was investigated in 61 MBC patients from discovery cohort who had been radiographically examined after first complete cycle of chemo therapy. We found a robust association between high plasma HA level and poor prognosis of MBC patients in both discovery (p(PFS)=7.92 x 10(-6) and p(OS)=5.27 x 10(-5)) and validation studies (p(PFS)=3.66 x 10(-4) and p(OS)=1.43 x 10(-4)). In the discovery cohort, the plasma HA level displayed independent prognostic value after adjusted for age and clinicopathological factors, with respect to PFS and OS. Further, the decrease of plasma HA level displayed good concordance with treatment response evaluated by radiographic examination (AUC=0.79). Plasma HA level displays prognostic value, as well as treatment monitoring value for MBC patients. What's new? Few markers can predict patient survival from the time of early disease dissemination in metastatic breast cancer (MBC), the cause of most breast cancer deaths. However, it may be possible to improve survival and quality of life in MBC with prognostic markers that are noninvasive and more specific. A promising candidate is hyaluronic acid (HA), elevated plasma levels of which are shown here to be significantly associated with poor prognosis of MBC patients. HA plasma levels decreased in parallel with treatment response, suggesting that HA may also be an effective real-time marker for MBC treatment-monitoring.