Background: Headaches are one of the most frequent reasons for pain in multiple sclerosis (MS) individuals. Characterization of headaches and delineating possible relationships with MS-related determinants can ultimately circumvent headaches.Methods: In a prospective case-control study, 65 Iranian relapsing- remitting MS (RRMS) patients and 65 healthy controls were recruited during patients’ admission for attack-period treatment and asked about characteristics and co-symptoms of headaches they experienced in the preceding week and usage of disease modifying drugs (DMDs) and types of MS attacks were also inquired. The same questions were asked from the same patients 3 months later in a follow-up visit.Results: A total of 57 patients and 57 controls were included in the final analyses. In total, 26 (45.6%) patients in relapse, 18 (27.7%) controls, and 22 (38.6%) patients in remission reported headaches and only significant difference existed between relapse patients and controls (P = 0.036). In headache prevalence was higher in patients in relapse phase having MS < 3 years compared to relapse patients with more than 3 years of MS (68 vs. 28.1%; P = 0.004). Other variables of interest did not differ among the three groups.Conclusion: The RRMS patients in relapse phase suffer from headaches more than healthy people do.