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Given that sleep disturbance and fatigue are pervasive among patients with advanced ovarian cancer (OC) and associated with poor health-related quality of life (HRQoL), several patient-reported outcome measures have been used to assess symptom burden. However, it remains unclear which patient-reported topic domains are most important to HRQoL for advanced OC patients. This study aimed to assess the domains of sleep disturbance and fatigue associated with poor HRQoL among patients with advanced OC across their treatment trajectory. We conducted an online survey with adults diagnosed with Stage III or IV OC in the last three years. Patients reported clinical and sociodemographic characteristics, sleep disturbance and fatigue levels using Patient-Reported Outcomes Measurement Information System (PROMIS) short forms, and HRQoL using the CDC Healthy Days measure. Hierarchical regression models were used to assess how sleep disturbance and fatigue short-form items predicted poor HRQoL, specifically the number of days where poor health interfered with daily life and poor physical and mental health days (unhealthy days) in the past month, compared to clinical (time since treatment, treatments received, metastatic status) and sociodemographic (age, gender, marital status, employment) factors. Among the 200 participants diagnosed with advanced OC (71.50% Stage III, 28.50% Stage IV; 33.50% receiving chemotherapy, 44.00% receiving maintenance therapy), sleep disturbance and fatigue were significantly associated with poor HRQoL. Compared to clinical and sociodemographic variables, sleep disturbance levels explained 17.00% more variance in the number of unhealthy days in the past month; fatigue levels explained 30.00% more variance in the number of unhealthy days. Among short form items, having difficulty falling asleep (β = 0.17, p = .03), fatigue interfering with physical function (β = 0.24, p < .01), and feeling run-down (β = 0.35, p < .01) were the strongest predictors of poor HRQoL. Patients with advanced OC reported significantly elevated levels of sleep disturbance and fatigue, which were associated with poor physical and mental health. Findings highlight the importance of screening for difficulty falling asleep, interference with physical function, and feeling run-down to connect patients with supportive care that may improve their HRQoL during and after treatment. Many people with ovarian cancer have trouble sleeping and experience fatigue, which make their quality of life worse. Healthcare providers have limited time with patients, so it can be difficult to identify and treat the symptoms that matter most to patients’ quality of life. In this study, we identified the issues that patients with ovarian cancer had with sleeping and fatigue that were most important to their quality of life by having them answer questions on a survey. We discovered that patients who said that they most often had difficulty falling asleep had a worse quality of life. Patients who said that fatigue often got in the way of doing physical activities and felt run-down also had poorer quality of life. This study demonstrated that there are three symptoms associated with difficulty sleeping and fatigue that are most important to ovarian cancer patients’ quality of life. During and after treatment, healthcare providers should ask people with ovarian cancer how much trouble they have falling asleep, how much fatigue gets in the way of doing physical activities, and how much they feel run-down. Asking these questions can help people get the support they need to improve their sleep and fatigue issues.