The authors describe a patient who was suspected of having cutaneous T cell lymphoma involvement of the brain despite repeatedly negative cerebrospinal fluid (CSF) cytology, inconclusive flow cytometry, and no discrete lesion for brain biopsy. The diagnosis was made by polymerase chain reaction (PCR) analysis that showed a monoclonal T cell receptor gamma-chain gene rearrangement in the CSF, identically sized to that present in a skin biopsy specimen. Thus, PCR could be used early and routinely to diagnose central nervous system spread of T cell lymphomas, because of its potentially superior sensitivity and specificity to CSF cytology.