OBJECTIVE Fatigue is a common and debilitating late-term effect of breast cancer that is associated with poor sleep and decreased quality of life, yet therapies remain limited. Acupressure has reduced fatigue in previous small studies, but rigorous clinical trials are needed. OBJECTIVE To investigate if 6 weeks of 2 types of self-administered acupressure improved fatigue, sleep, and quality of life vs usual care in breast cancer survivors and to determine if changes were sustained during a 4-week washout period. METHODS Phase 3 randomized, single-blind, clinical trial conducted from March 1, 2011, through October 31, 2014. Women were recruited from the Michigan Tumor Registry. METHODS Randomization (1:1:1) to 6 weeks of daily self-administered relaxing acupressure, stimulating acupressure, or usual care. METHODS The primary outcome was change in the Brief Fatigue Inventory score from baseline to weeks 6 and 10. Secondary analyses were sleep (Pittsburgh Sleep Quality Index) and quality of life (Long-Term Quality of Life Instrument). RESULTS A total of 424 survivors of stages 0 to III breast cancer who had completed cancer treatments at least 12 months previously were screened, and 288 were randomized, with 270 receiving relaxing acupressure (n = 94), stimulating acupressure (n = 90), or usual care (n = 86). One woman withdrew owing to bruising at the acupoints. At week 6, the percentages of participants who achieved normal fatigue levels (Brief Fatigue Inventory score <4) were 66.2% (49 of 74) in relaxing acupressure, 60.9% (42 of 70) in stimulating acupressure, and 31.3% (26 of 84) in usual care. At week 10, a total of 56.3% (40 of 71) in relaxing acupressure, 60.9% (42 of 69) in stimulating acupressure, and 30.1% (25 of 83) in usual care continued to have normal fatigue. At neither time point were the 2 acupressure groups significantly different. Relaxing acupressure, but not stimulating acupressure, showed significant improvements in sleep quality compared with usual care at week 6, but not at week 10. Only relaxing acupressure significantly improved quality of life vs usual care at weeks 6 and 10. CONCLUSIONS Both acupressure arms significantly reduced persistent fatigue compared with usual care, but only relaxing acupressure had significant effects on sleep quality and quality of life. Relaxing acupressure offers a possible low-cost option for managing symptoms. BACKGROUND clinicaltrials.gov Identifier: NCT01281904.