BACKGROUND: Fatigue is a common problem in individuals with multiple sclerosis (MS). OBJECTIVE: The objective was to evaluate the effects on fatigue of having 4 weeks of access to audio recordings of therapeutic hypnosis (HYP) and mindfulness meditation (MM) practices. METHODS: A total of 333 individuals with MS and fatigue were randomly assigned to one of the three treatment conditions for 28 weeks: (1) access to therapeutic HYP audio recordings, (2) access to MM audio recordings, or (3) no access to recordings (treatment as usual or TAU). Fatigue impact (primary outcome) and other outcomes were assessed at 4, 16, and 28 weeks after random assignment. RESULTS: Participants assigned to the HYP and MM conditions reported significantly greater reductions in fatigue impact, sleep disturbance, and depressive symptom severity than participants assigned to the TAU condition after 4 weeks of access to audio recordings of these interventions. These improvements were maintained for 16 and 28 weeks following initial access and did not result in any serious adverse events. CONCLUSION: Given the ease with which audio recordings of HYP and MM could be provided to individuals with MS, the findings support the feasibility of a simple approach to have a significant beneficial impact on people with MS-related fatigue.