The present study has explored the possible value of sCA-125 as a prognostic factor in Hodgkin's lymphoma (HL). From August 1992 to June 2005 sCA-125 was measured at presentation and at the end of the treatments in 221 newly diagnosed adult patients with HL. In this study 90/221 (41%) patients showed a value greater than the standard upper limit of 35 U/ml, and 79/90 (88%) with an abnormal sCA-125 were at an advanced stage of the disease. Patients with elevated sCA-125 showed a significant reduction in complete remission (CR) rate (76%vs. 98%; p < 0.0001). Failure of normalization of sCA-125 during the treatment revealed that CR had not been reached. Furthermore, no traces of the glycoprotein sCA-125 were found in a series of paraffin-embedded samples coming from 15 patients of this study. In addition, soluble CA-125 was not detected in supernatants coming from four different Hodgkin-derived cell lines. The long-term follow-up revealed that the group of patients with sCA-125 lower than 35 U/ml, at diagnosis, had an estimated 92% event free survival (EFS) rate and a 94% overall survival (OS) rate, while the group of patients with sCA-125 greater than 35 U/ml had only a 60% EFS rate (log-rank 33.43, p < 0.0001) and a 70% OS rate (log-rank 23.52, p < 0.0001). Extranodal disease, severe lymphocytopenia and age proved to be the only standard factors that could represent a poor chance to survive. At multivariate analysis, high sCA-125, E sites >1 and age were the only independent factors producing poor outcomes in terms of CR, EFS and OS. Therefore, we believe that sCA-125 is a simple, reliable and reproducible tool, which may improve existing prognostic systems.