OBJECTIVE To study the presenting features and value of routine diagnostic procedures in patients with leptomeningeal metastases (LMM) related to the primary malignancy to improve diagnostic assessment. METHODS The authors studied the presenting features and value of routine diagnostic procedures in relation to the histology of primary malignant disease in 45 patients with LMM of solid (n = 30) or hematologic (n = 15) malignancies. RESULTS Patients with solid LMM present mostly with spinal or radicular symptoms (53%), whereas patients with hematologic LMM more often show cranial nerve dysfunction at presentation (53%). Multifocal neurologic symptoms were seen in 67% of patients. The first CSF cytology demonstrated malignant cells more frequently in solid LMM compared with hematologic LMM (73% versus 53%). Extralumbar punctures increased the sensitivity of cytology to a greater extent in hematologic LMM than in solid LMM (34% versus 10%). Abnormal neuroimaging findings were found more often in solid LMM than in hematologic LMM (67% versus 40%). Increased total CSF protein in combination with either multifocal neurologic symptoms or abnormal neuroimaging findings was found in 73% of patients with a negative first CSF cytology. CONCLUSIONS Patients with LMM presented differently depending on the histology of the primary tumor. In patients with a negative first CSF cytologic examination, multiple lumbar punctures increased the diagnostic accuracy, especially in hematologic LMM. LMM could also be diagnosed in patients with known cancer if total CSF protein was increased in combination with either multifocal neurologic symptoms or abnormal neuroimaging findings, preferably MRI.