OBJECTIVE: Cancer-related fatigue (CRF) is one of the most common, persistent, and disabling symptoms associated with cancer and its treatment. Evidence-based treatments that are acceptable to patients are critically needed. This study examined the efficacy of mindfulness-based stress reduction (MBSR) for CRF and related symptoms. METHOD: A sample of 35 cancer survivors with clinically significant CRF was randomly assigned to a 7-week MBSR-based intervention or wait-list control group. The intervention group received training in mindfulness meditation, yoga, and self-regulatory responses to stress. Fatigue interference (primary outcome) and a variety of secondary outcomes (e.g., fatigue severity, vitality, disability, depression, anxiety, and sleep disturbance) were assessed at baseline, post-intervention, and 1-month follow-up. Bonferroni correction was employed to account for multiple comparisons. Controls received the intervention after the 1-month follow-up. Participants in both groups were followed for 6 months after completing their respective MBSR courses to assess maintenance of effects. RESULTS: Compared to controls, the MBSR group reported large post-intervention reductions as assessed by effect sizes (d) in the primary outcome, fatigue interference (d = -1.43, p < 0.001), along with fatigue severity (d = -1.55, p < 0.001), vitality (d = 1.29, p < 0.001), depression (d = -1.30, p < 0.001), and sleep disturbance (d = -0.74, p = 0.001). Results were maintained or strengthened at 1-month follow-up, the point at which significant improvements in disability (d = -1.22, p < 0.002) and anxiety (d = -0.98, p = 0.002) occurred. Improvements in all outcomes were maintained 6 months after completing the course. MBSR adherence was high, with 90% attendance across groups and high rates of participant-reported home practice of mindfulness. CONCLUSIONS: Mindfulness-based stress reduction is a promising treatment for CRF and associated symptoms.