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Introduction: Amyotrophic lateral sclerosis (ALS) is a fatal progressive neurodegenerative disease resulting in the dysfunction of upper and lower motor neurons. Biomarkers in fluid have been used to monitor the disease and its progression. Milk fat globule-EGF factor 8 (MFG-E8) is an inflammation modulator, which is involved in the pathogenesis of neurodegenerative diseases. We here took this study to evaluate the predictive value of MFG-E8 in ALS., Methods: This study consisted of 19 patients with ALS and 15 healthy controls. Cerebrospinal fluid (CSF) were collected from all participants and tested for the levels of MFG-E8, neurofilament light (NFL), and heavy chain (NFH). The correlations between MFG-E8 and NFL, NFH, ALS severity, cognitive status, and forced vital capacity (FVC) were analyzed., Results: We found that MFG-E8 performs well in distinguishing ALS from controls, with relatively higher level of MFG-E8 in ALS subjects, than controls. Moreover, MFG-E8 negatively correlated with the revised ALS function rating scale (ALS-FRS), but not with the levels of NFL and NFH, disease duration, progression rate, mini-mental state examination (MMSE), and FVC., Conclusions: The study proved that CSF MFG-E8 helps distinguish ALS from controls. However, the protein in CSF negatively predicted disease severity.