Syndecan-1 (CD138) is a heparin sulphate proteoglycan that is over expressed on the surface of both normal and malignant plasma cells and actively shed from the cell surface (soluble syndecan-1). Soluble syndecan-1 has been shown to be an independent prognostic factor in myeloma but its role in prognostic classification requires further investigation. We have retrospectively measured soluble syndecan-1 in 324 presentation samples and 154 plateau phase samples from the UK Medical Research Council Myeloma VIth trial. Log-rank analysis showed that the presentation value of soluble syndecan-1 is a highly significant prognostic factor when assessing survival from entry (chi2=14.92, P<0.0001) and remains an important independent prognostic factor when considered in Cox regression models (P<or=0.02) with known independent factors. The magnitude of fall in soluble syndecan-1 from presentation to plateau also had prognostic value when assessing overall survival from plateau (chi2=3.79, P=0.05). In conclusion, this large study confirms that soluble syndecan-1 level is a powerful independent prognostic factor both at diagnosis and at plateau phase.