Malignant and nonmalignant serosal fluids have been found to be associated with high serum levels of CA 125, suggesting that the presence of fluid in the serosal cavities may stimulate its release. In this study, we investigated the relationship between serum CA 125 levels and the presence of pleural fluid in patients with chronic heart failure (CHF). We performed a clinical study in 36 patients with CHF with and without pleural fluid. Patients with CHF were divided into two groups based on the presence of fluid in the pleural cavity. Group 1 included 18 CHF patients (6 females, 12 males) with pleural fluid. Group 2 consisted of 18 CHF patients (7 females, 11 males) without pleural fluid. The control group consisted of 30 healthy volunteers (12 females, 18 males). The serum CA 125 level was determined in all groups. Serum CA 125 levels were found to be 100.0 ± 129.4 U/ml in CHF patients with pleural fluids, whereas they were 36.5 ± 35.2 U/ml in CHF patients without pleural fluid and 8.9 ± 6.1 U/ml in the control group. Significantly high serum CA 125 levels were found in CHF patients with pleural fluids (p < 0.05) when compared with both CHF patients without pleural fluid and the control group. There was also a statistically significant difference in CA 125 levels between patients without pleural fluid and the control group (p < 0.05). We concluded that serum CA 125 levels should be interpreted with caution in patients with CHF in the presence of pleural fluid. Invasive procedures to define the etiology of elevated serum CA 125 levels may be unnecessary in this patient group. Copyright © 2003 S. Karger AG, Basel.