Serum CA-125 level has been shown to be elevated in patients with non-Hodgkins lymphomas (NHLs) and it is proposed that cytokines released by lymphoma cells activate mesothelial cells to secrete this glycoprotein. Aim of Study: The aim was to evaluate whether serum CA-125 levels vary with extranodal extension and disease staging of Egyptian NHL patients Patients and Methods: 117 adult patients with NHL were included, and based on the patients available laboratory (CBC, ESR, liver enzymes, LDH), radiological (CT scans and PET scanning), and pathological (reports of biopsies obtained from affected lesions) investigations, the sites of lesions (nodal and/or extranodal), disease staging (from stage I to IV), and performance status PS (from PS-0 to PS-5) were determined at patients presentation. Serum CA-125 levels were estimated for all studied patients. Results:Mean serum CA-125 level in all studied patients was 59.2?17.8 u/mL, with no significant differences between males and females. Patients with PS-3 had higher serum CA-125 levels than patients with PS-2 and PS-1. Serum CA-125 levels were significantly higher in patients presented with B symptoms (125.9?31.2 u/mL) compared to those with no B symptoms (57.2?18.7 u/mL). Serum CA-125 levels showed significant positive non-linear correlation with the disease stages, where the mean serum CA-125 levels in patients with stage-I NHL was 51.7?15.2 u/mL, stage-II was 61.3?17.6 u/mL, stage-III was 93.1?31.8 u/mL, and stage-IV was 167.1?59.6 u/mL.Mean serum CA-125 levels in patients with extranodal lesions only (217.1?47.9 u/mL) and in patients with both nodal and extranodal lesions (198.2?41.7 u/mL) were significantly higher compared to its levels in patients with nodal lesions only (51.7?16.3 u/mL). Conclusion and Recommendations: In NHL patients, the presence of B symptoms, advancing stages of disease, and extranodal lesions were associated with higher serum C-125 levels. Further studies are recommended to set a cut-off point for using serum CA-125 levels as an indicator for NHL extranodal lesions.