The main cause of trigeminal neuralgia (TN) is compression of a blood vessel at the root entry zone of the trigeminal nerve. However, a neurovascular conflict does not seem to be the only etiology and other mechanisms are implicated in the development of the disease. We hypothesized that TN patients may have distinct protein expression in the CSF. In this study, lumbar CSF from TN patients (n=17), scheduled to undergo microvascular decompression (MVD), and from controls (n=20) was analyzed and compared with mass spectrometry-based shotgun proteomics. 2552 unique proteins were identified of which 46 were significantly altered (26 increased, and 20 decreased, q-value < 0.05) in TN patients compared with controls. An over-representation analysis showed proteins involved in high-density lipoprotein (HDL), such as APOA-4, APOM and APOA-1, and the extracellular region, including proteins involved in the complement cascade to be over-represented. We conclude that TN patients have distinct protein expression in the CSF compared to controls. The pathophysiological background of the protein alterations found in this study warrants further investigation in future studies. Perspective: In this article, cerebrospinal fluid from patients with trigeminal neuralgia was analyzed using in depth shotgun proteomics, revealing 46 differentially expressed proteins compared to controls. Among these, apolipoproteins and proteins involved in the complement system were elevated and significantly over-represented, implying an inflammatory component in the pathophysiology of the disease.