Background: IL-27 acts as a ‘master regulator’ in modulating inflammation and was responsible for a number of autoimmune diseases. However, the role of IL-27 was not addressed in Guillain-Barré syndrome (GBS). Methods: Sixty-five subjects including 19 with GBS, 7 with encephalitis or meningitis, 23 with multiple sclerosis or neuromyelitis optica as well as 11 with other non-inflammatory neurological disorders were enrolled. ELISA was used to detect the concentrations of IL-27 in paired samples of cerebrospinal fluid and plasma. Results: The mean concentration of IL-27 in GBS patients was significantly lower than in other neurological disorders both in CSF and in plasma (all p<0.05). GBS patients with cranial involvement, decreased reflexes, hypaesthesia, autonomic nerve dysfunction, MRC score <30 are inclined to have a lower CSF IL-27 level than patients without these symptoms (182 pg/ml, 181 pg/ml, 185 pg/ml, 185 pg/ml, 194 pg/ml vs 211 pg/ml, 205 pg/ml, 202 pg/ml, 198 pg/ml, 199 pg/ml, respectively). Similar results were noted in plasma except for cranial involvement. Conclusions: Production of IL-27 was disparate between GBS and other neurological diseases and a significantly lower level of IL-27 was observed in GBS patients, indicative of an anti-inflammatory role of IL-27 in GBS.