Fatigue is common amongst patients with multiple sclerosis (MS), but it is poorly understood. This study examined sleepiness and sleep-related factors using polysomnography. This cohort-controlled, ethics-approved, pilot study compared 12 MS patients, divided into two groups (with and without daytime sleepiness — assessed with the Epworth Sleepiness Scale [ESS], Fatigue Severity Scale, and Fatigue Impact Scale), with 14 controls presenting for assessment of fatigue. All underwent polysomnography, with MS patients also undergoing multiple sleep latency testing, drug screening, and expanded disability-status scale evaluation. Statistical analysis used non-parametric comparisons. Based on the ESS, with the cut-off being ≤9, the two subgroups of MS patients were well matched for all criteria except sleepiness. Comparison between the 12 MS patients and 14 controls showed statistical difference for minimum oxygen saturation (P = 0.0316), periodic limb movement in sleep (PLMS) with arousal (PLMA) (P = 0.0387), time in non-REM sleep (P = 0.0308), latency REM (P = 0.0101), and mean duration of hypopneas/apneas (P = 0.0453). Comparing MS patients with ESS > 9 with controls eliminated these differences, suggesting that lack of sleepiness was causative. There was a trend to difference between the two groups of MS patients for apnea/hypopnea index, duration of apnea/hypopnea, and PLMS with statistical difference for PLMA (P = 0.0447). This study showed a significant relationship between PLMA and sleepiness (or fatigue) in MS, evoking potential therapies. Trends for other variables justify larger studies. Our study cast doubt on Fatigue Severity Scale and Fatigue Impact Scale as reflective of fatigue, with excessive sleepiness possibly being more relevant than has been previously appreciated.