Narcolepsy type 1 is a devastating neurological sleep disorder resulting from the destruction of orexin-producing neurons in the central nervous system (CNS). Despite its striking association with the HLA-DQB1*06:02 allele, the autoimmune etiology of narcolepsy has remained largely hypothetical. Here, we compared peripheral mononucleated cells from narcolepsy patients with HLA-DQB1*06:02-matched healthy controls using high-dimensional mass cytometry in combination with algorithm-guided data analysis. Narcolepsy patients displayed multifaceted immune activation in CD4(+) and CD8(+) T cells dominated by elevated levels of B cell-supporting cytokines. Additionally, T cells from narcolepsy patients showed increased production of the proinflammatory cytokines IL-2 and TNF. Although it remains to be established whether these changes are primary to an autoimmune process in narcolepsy or secondary to orexin deficiency, these findings are indicative of inflammatory processes in the pathogenesis of this enigmatic disease.