Background: Cancer and its treatment produce interrelated symptoms of sleep disturbance and fatigue, which are significantly correlated with diminished QOL, allowing for the possibility that improvement in these symptoms could improve QOL. We previously showed from a 2-arm phase III RCT that YOCAS Yoga improved sleep quality and fatigue compared to standard care in cancer survivors with disturbed sleep. Herein, we performed secondary analyses to examine (i) the effect of YOCAS Yoga on QOL and (ii) the mediating effects of changes in sleep and fatigue on QOL. Methods: Study assessments were performed on 245 female breast cancer survivors (mean age 54) prior to the 4-week Yoga intervention (baseline) and at post-intervention. Sleep was assessed by the Pittsburgh Sleep Quality Inventory (PSQI) and the Insomnia Severity Index (ISI). Fatigue and QOL were assessed by individual items on the Symptom Inventory (SI, 0 = none to 10 = worst scale). QOL was also assessed by the Functional Assessment of Cancer Therapy-General (FACT-G). Simple change scores from baseline to post were calculated for all measures for patients who did (N = 123) or did not (N = 122) receive Yoga. Results: QOL scores at baseline and post for the Yoga group were: SI-QOL: 3.6, 2.5 and FACT-G: 79.7, 82.8, and for the non-Yoga group were: SI-QOL: 3.4, 3.4 and FACT-G: 77.5, 78.4. ANCOVA controlling for baseline showed significantly better scores on both QOL measures at post in the Yoga group than non-Yoga group (both p’s ≤ 0.01). Changes over time in the SI-QOL and FACT-G were significantly associated with concurrent changes in the PSQI, ISI and SI-Fatigue (all R’s ≥ 0.29; all p’s < 0.0001). Linear regression showed that one unit improvements in the PSQI, ISI, and SI-Fatigue were associated with an improvement in SI-QOL of 0.14, 0.11, and 0.21, respectively (all p’s ≤ 0.01) and FACT-G of -0.83, -0.89, and -2.0, respectively (all p’s ≤ 0.001). Conclusions: In breast cancer survivors with sleep disturbance, Yoga significantly improved QOL and this improvement in QOL may be mediated by concurrent improvements in sleep disturbance and fatigue. Further research is needed to confirm these findings. Funding: NCI grants 1R01CA181064, R25CA10618 and UG1CA189961. Clinical trial information: NCT00397930