Background: We previously reported that, in Japanese patients with multiple sclerosis (MS), the frequency of chronic headaches was signifi cantly higher after administration of interferon beta (IFNβ). However, the mechanisms underlying IFNβ-related chronic headaches were unknown. Objective: To clarify the mechanisms underlying IFNβ-induced chronic headaches in MS patients by analyzing cytokine levels in cerebrospinal fl uid (CSF). Methods: We measured the levels of 27 CSF cytokines and growth factors using a fl uorescent bead-based immunoassay, during a headache-free period, in 34 MS patients enrolled in our previous survey on chronic headaches. Results: There were no signifi cant differences in CSF cytokine levels between the 21 MS patients with chronic headaches and the 13 without chronic headaches. Among the 14 patients receiving IFNβ therapy, the 5 patients with chronic headaches showed signifi cantly lower levels of interleukin (IL) 15, IL17 and chemokine (C-C motif) ligand 2 (CCL2) (also known as monocyte chemoattractant protein 1; MCP1) compared with the 9 patients without chronic headaches (P < 0.05). Conclusions: The present survey revealed that in MS, chronic headache sufferers on IFNβ therapy had decreased levels of IL15, IL17 and CCL2 in CSF. This suggests that chronic headaches may tend to develop in good responders to IFNβ.