Epilepsy research efforts have primarily focused on medical treatment and physical management of epilepsy; however, to provide comprehensive care, efforts cannot focus solely on physical manifestations of epilepsy. Research findings show that people with epilepsy face many challenges that can negatively affect quality of life (QOL). In this descriptive study, we examined the individual relationships between depressive symptoms, stigma, social support and regimen-specific support and QOL in adults with epilepsy. Study data were obtained from a subset of patients (N = 147) who participated in a longitudinal study of adult patients with epilepsy. Measures of QOL, depressive symptoms, stigma, social support and regimen-specific support were analyzed to answer the research questions. The results of correlational analyses revealed statistically significant negative correlations between depressive symptoms, stigma and sometimes regimen-specific support and QOL and statistically significant positive correlations between social support and QOL. A hierarchical multiple linear regression model revealed that depressive symptoms accounted for the most variance in QOL. Psychosocial variables measured 3 months prior to QOL were entered into a hierarchical multiple linear regression model, revealing that depressive symptoms, stigma and social support can be used to predict QOL at a later time.