Objective: The goal of this study was to examine the effects of age, age at seizure onset, and duration of epilepsy on health-related quality of life (HRQOL) in patients with medication-resistant epilepsy. Methods: We analyzed data for a sample of 99 patients with medication-resistant epilepsy drawn from admissions to the Epilepsy Monitoring Unit. Patients had completed the Quality of Life in Epilepsy-89 (QOLIE-89), Profile of Mood States (POMS), and Adverse Events Profile. Number of comorbidities and number of antiepileptic drugs were abstracted from the chart. The dependent variable was QOLIE-89 overall score. The data were analyzed using ordinary least-squares regression. Results: The simple regression results showed no significant effect of patient's age on QOLIE-89 (P = 0.354), whereas age at onset and duration had significant effects (P = 0.004 and P = 0.012, respectively); the higher the age at onset and the shorter the disease duration, the lower the HRQOL. After adding POMS Depression/Dejection, Adverse Events Profile, comorbidities, and antiepileptic drugs, the effects of age at onset and duration were no longer significant (P = 0.084 and P = 0.207). Conclusions: Adult-onset epilepsy can disrupt one's established social, economic, and psychological life, while better coping mechanisms and social support may improve HRQOL as the duration of epilepsy increases. The modest association of age at onset and disease duration with HRQOL is explained away by mood states and adverse events, which are much stronger predictors of HRQOL. Interventions to improve HRQOL in patients with medication-resistant epilepsy should, therefore, focus on treating mood disturbances and minimizing medication side effects. © 2006 Elsevier Inc. All rights reserved.