Various studies have suggested that a neurotoxic cerebrospinal fluid (CSF) profile could be implicated in amyotrophic lateral sclerosis (ALS). Here, we systematically review the evidence for CSF cytotoxicity in ALS and explore its clinical correlates. We searched the following databases with no restrictions on publication date: PubMed, Embase and Web of Science. All studies that investigated cytotoxicity in vitro following exposure to CSF from ALS patients were considered for inclusion. Meta-analysis could not be performed, and findings were instead narratively summarised. 28 studies were included in our analysis. Both participant characteristics and study conditions including CSF concentration, exposure time and culture model varied considerably across studies. Of 22 studies assessing cell viability relative to controls, 19 studies reported a significant decrease following exposure to ALS-CSF, while three early studies failed to observe any difference. Seven of eight studies evaluating apoptosis observed significant increases in the levels of apoptotic markers following exposure to ALS-CSF, with the remaining study reporting a qualitative difference. Although five studies investigated the possible relationship between CSF cytotoxicity and patient characteristics, such as age, gender and disease duration, none demonstrated an association with any of the factors. In conclusion, our analysis suggests that CSF cytotoxicity is a feature of sporadic and possibly also of familial forms of ALS. Further research is, however, required to better characterise its underlying mechanisms and to establish its possible contribution to ALS pathophysiology.