The authors investigated the diagnostic value of cerebrospinal fluid (CSF) soluble CD27 (sCD27) for leptomeningeal involvement of non-Hodgkin lymphomas (NHL). Cytospin slides were prepared from CSF samples of 64 children treated for NHL. sCD27 levels were determined by sandwich ELISA method using two CD27 monoclonal antibodies. 8/194 (4.1%) samples were considered tumor-positive by cytology. Mean sCD27 values were 5.8 and 13.8 U/mL in tumor-negative and tumor-positive samples, respectively (p = .18). 26/194 samples were false positive and 2/194 false negative (cutoff: 7 U/mL) (sensitivity, 75%; specificity, 86%; positive predictive value, 18.8%; negative predictive value, 98.8%; accuracy, 85.6%). With these results, the value of adding sCD27 determination to the cytological CSF examination remains questionable.