We evaluated the clinical use and the safety of cerebrospinal fluid diagnostics in 155 patients with the suspected diagnosis of first-episode schizophrenia. Five patients (3.2%) revealed pathological findings that lead to diagnostic re-evaluation and changes in clinical management. No serious adverse events occurred, but we documented 16 (10.3%) cases of mild to moderate headache or local pain at the puncture site. Our results underline the value of lumbar puncture in the clinical workup of first-episode patients with suspected schizophrenia.