Seizure-related head injury (SRHI) is an under-recognized condition frequently experienced by people with epilepsy (PWE). The purpose of this study is to investigate the potential impact of SRHI on health-related quality of life (HRQOL) among PWE receiving care in a tertiary epilepsy center. Consecutive adult PWE receiving care at the Baylor Comprehensive Epilepsy Center (BCEC) were recruited for the study. After their informed consent was obtained, patients were administered the QOLIE-31 to measure HRQOL and the NDDI-E to screen for depression. Simple linear regression was used to identify clinical variables associated with HRQOL and that included SRHI obtained systematically at each clinic visit. Data were also compared between the SRHI and non-SRHI groups. Participants included 172 subjects. Recurrent mild SRHI occurred in 50 (29%) subjects. Factors with a negative effect on HRQOL included depression (slope = -19.99 [95% CI -25.16, -14.81]; p < .0001), recurrent SRHI (-17.02 [-22.35, -11.69]; p < .0001), past SRHI (-13.46 [-18.43, -8.48]; p < .0001), and seizure frequency (-0.17 [-0.26, -0.07]; p = 0.001) on univariate analysis. With stepwise multiple regression, depression and recurrent SRHI significantly impacted HRQOL with slopes (95% CI; p-value) of (-17.53 [-22.34, -12.73]; p < .0001) and (-14.03 [-18.78, -9.28]; p < .0001), respectively. Patient-derived HRQOL is negatively associated with depression and recurrent SRHI, independently. There has been a justifiable increased awareness of the potential effects of head injuries among healthy individuals. Our data suggest that head injuries can certainly be detrimental among PWE, and greater efforts should be made to recognize and formulate prevention strategies for SRHI. (C) 2013 Elsevier Inc. All rights reserved.