An 80-year-old woman presented with fevers, night sweats, and weight loss. Her serum CA-125 level was markedly elevated (380 U/mL; normal < 35 U/ml). At post-mortem examination, the patient had widespread intermediate-grade malignant lymphoma with extensive infiltration of the greater omentum and pelvic peritoneum. Immunohistochemistry for CA-125 documented intense staining in the reactive mesothelial cells of the peritoneum; the tumor cells were not immunoreactive. CA-125 is a glycoprotein recognized by a monoclonal antibody raised against an ovarian-cancer cell line. Elevated levels have been reported rarely in patients with malignant lymphoma, and the pathophysiology of this finding has not been understood. Our data support the hypothesis that elevated CA-125 levels may reflect production by reactive mesothelium in patients with benign or malignant diseases involving the peritoneum, including malignant lymphoma. The clinical application of this marker, therefore, is broader than the recognized monitoring of patients with ovarian carcinoma.