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Objective: Neurocognitive functioning (NCF), mood disturbances, physical functioning, and social support all share a relationship with health-related quality of life (HRQOL). However, investigations into these relationships have not been conducted in persons with brain metastases (BM)., Patients and Methods: Ninety-three newly diagnosed persons with BM were administered various cognitive batteries. Data were collected across a wide range of categories (ie, cognitive, demographic, disease/treatment, mood, social support, physical functioning). The Functional Assessment of Cancer Treatment (FACT) scale was used to measure HRQOL., Results: Mood and physical function correlated with lower HRQOL in every measured domain. Verbal learning and memory correlated with every FACT subscale except emotional quality of life. Social support also correlated with several HRQOL domains. Stepwise linear regression revealed that mood predicted general well-being and several FACT subscales, including physical, emotional and cognitive well-being. Social support and physical health were predictive of general well-being. Verbal learning and memory predicted cognitive well-being., Conclusion: HRQOL is a complex construct affected by numerous variables. In particular, mood, physical functioning, and learning and memory were important predictors of HRQOL, and clinicians are encouraged to obtain information in these areas during baseline assessments in persons with BM., (© 2020 John Wiley & Sons, Ltd.)