We studied the use of fluorescence in situ hybridization (FISH) in CSF to enhance the diagnostic yield for the detection of malignancy on the first lumbar puncture in patients clinically suspected of having leptomeningeal metastases (LMM). Although repeated lumbar punctures were still needed in some patients, the use of FISH did speed up the diagnosis in approximately one-third of the patients clinically suspected of having LMM with atypical cells at first cytology. This eliminates the need for repeated lumbar punctures in these patients and enables an earlier start of treatment.