BACKGROUND: Sleep disturbances are highly prevalent in people with multiple sclerosis(MS), and are associated with pain, fatigue, depression, and reduced quality of life (QoL). Importantly, sleep has been considered a critical brain state for motor learning and memory consolidation. Therefore, interventions that target sleep managementin people with MS are needed. OBJECTIVES: To explore the effects of a six weeks moderate-intensity aerobic exercise intervention on sleep characteristics and sleep-related biomarkers specifically serotonin, melatoninand cortisol in people with MS using a pilot randomized controlled trial. METHODS: Participants were randomly allocated to either a moderate-intensity aerobic exercise program (MAE, n = 20) or a home exercise program (HEP, n = 20). Participants were assessed at baseline and follow-up. Subjective and objective measures were used to assess sleep quality. The Pittsburgh Sleep Quality Index (PSQI) and Insomnia Severity Index (ISI) were used to subjectively assess sleep. While Actigraphy was used to objectivelyassess sleep. Blood samples were collected for measurement of cortisol, melatonin and serotonin from MS participants in both groups at 8:00 am±1 hour. RESULTS: Seventeen participants in the MAE and 13 in the HEP group completed the study. Compared to the HEP group, people with MS who participated in a moderate-intensity aerobic exercise experienced significant improvements (P < 0.05) on the PSQI, ISI, and several objective sleep parameters measured using actigraphy. Only the serotonin levels increased significantly over the six-week period in the MAE group compared to the HEP group. The change score in serotonin (from baseline to follow up assessment) was significantly correlatedwith the change score in PSQI (r = -0.97, p < 001) and the change score in ISI (r = -0. 56, p = 0.015) only in the MAE group but not the HEP group. CONCLUSIONS: Exercise may be a non-pharmacological, inexpensive, safe method to improve sleep quality in people with MS. The improvement in the serotonin level due to aerobic exercisemight explain one of the physiologic mechanisms driving these improvements.