CONTEXT: Patients who are prognostically aware are more likely to receive end-of-life care consistent with their values. However, prognostic awareness has shown mixed associations with patients' quality-of-life (QoL) outcomes. Theory suggests that acceptance of cancer may moderate relationships between prognostic awareness and outcomes of QoL and end-of-life treatment preferences. Patients' degree of prognostic awareness and illness acceptance may also impact their family caregivers' QoL and end-of-life treatment preferences for the patient. OBJECTIVES: To examine the potential moderating role of patient acceptance of cancer in the relationships between patient prognostic awareness and both patient and caregiver QoL and end-of-life treatment preferences. METHODS: A cross-sectional, secondary analysis was conducted using data from patients with advanced cancer (n=243) and their caregivers (n=87) in the multi-institutional Coping with Cancer-II cohort study. Patient physical, psychological, and existential QoL were examined in a moderation path analysis. Caregiver physical and psychological QoL were examined in separate linear regression analyses. Patient and caregiver end-of-life treatment preferences were examined in multiple logistic regression moderation models. RESULTS: No significant moderations were found. Greater patient illness acceptance was associated with better patient QoL outcomes and caregiver psychological QoL but was unrelated to end-of-life treatment preferences. Greater patient prognostic awareness was associated with worse patient physical QoL and both patients' and caregivers' preference for comfort care. CONCLUSION: Increasing patients' prognostic awareness and cancer acceptance may improve values-consistent end-of-life care and patient and caregiver QoL outcomes. Findings support timely conversations to promote prognostic awareness and further testing of acceptance-based interventions in advanced cancer.