Measurement of biochemical markers represents an important aid to clinicians in the early diagnosis and prognosis of neurological diseases. Many factors can contribute to increase the chances that a biomarker study becomes successful. In a cerebrospinal fluid analysis (CSF), more than 84% of laboratory errors can be attributed to several preanalytical variables that include CSF collection, storage, and freeze thawing cycles. In this concept paper, we focus on some critical issues arising from basic proteomics investigation in order to highlight some key elements of CSF quality control. Furthermore, we propose a direct assessment of sample quality (DASQ) by applying a fast MALDI-TOF-MS methodology to evaluate molecular features of sample degradation and oxidation. We propose DASQ as a fast and simple initial step to be included in large-scale projects for neurological biomarker studies. In fact, such a procedure will improved the development of standardized protocols in order to have well-characterized CSF biobanks.