Diagnosis of central nervous system (CNS) lymphoma remains a challenge. This study aimed to identify cerebrospinal fluid (CSF) proteins that distinguish patients with and without CNS lymphoma. We used one-dimensional SDS-polyacrylamide gel electrophoresis coupled with liquid chromatography- electrospray ionization-quadrupole-time of flight-mass spectrometry (LC-ESI-Q-TOF MS) to identify CSF proteins in CNS diffuse large B cell lymphoma (DLBCL) patients and controls. Approximately 166 CSF proteins were identified, 12 for the first time in the CSF of lymphoma patients. Three proteins with significantly increased expression in CNS lymphoma patients compared with controls - haemopexin, apolipoprotein A1, and transferrin were verified by immunohistochemistry, and found to be strongly expressed in CNS DLBCL and nodal DLBCL. These proteins were found to be localized in the cytoplasm of a human DLBCL cell line by indirect immunofluorescence. ELISA confirmed expression at higher concentrations in the CSF of CNS lymphoma patients. CSF haemopexin, apolipoprotein A1, and transferrin concentrations were detected in CNS lymphoma patients and had diagnostic sensitivities of 80%, 83%, and 70%, and specificities of 75%, 89%, and 90%, respectively. Our study suggests that CSF proteins may be potential diagnostic biomarker for CNS lymphoma, especially for patients in which imaging and cytology do not provide a clear diagnosis.