The release of soluble forms of CD80 provides a potentially powerful mechanism for the modulation of anti-tumor responses. In this report we investigated whether a soluble form of CD80 (sCD80) circulates in vivo and whether levels are altered in patients with hematological malignancies. Circulating sCD80 was detected by ELISA in all normal donor (0.024-0.318 ng/ml) and patient (0.02-3.75 ng/ml) blood analyzed. The majority of acute myeloid leukemia (13/17) and multiple myeloma (11/12) patients had normal sCD80 levels. Significantly elevated levels were detected in chronic lymphocytic leukemia (CLL, P = 0.0001) and mantle cell lymphoma (MCL, P = 0.0002) patients. MCL patients had the highest levels with 8/9 having levels > 0.318 ng/ml. Increased sCD80 levels in CLL were significantly associated with poor prognosis markers such as low platelet (P = 0.01) and hemoglobin (P = 0.002) levels, elevated WBC counts (P = 0.03) and expression of CD38 (P = 0.048). The immunoreactivity of the sCD80 in both normal and patient plasma was inhibited by the presence of CTLA-4-Ig, suggesting sCD80 is functional. Comparison of sCD80 and soluble CD86 levels demonstrated that these molecules were independently elevated in 39% of patients. The finding that a proportion of CLL and the majority of MCL patients contain elevated levels of sCD80 and the demonstration that sCD80 can interact with CTLA-4-Ig suggests a potential role for sCD80 in modulating anti-tumor responses during the malignant process.