BackgroundHealth-related quality of life (HRQOL) is used as a measure of treatment outcomes, in addition to seizure control. Hence, the study was aimed to assess HRQOL and its determinants among adult patients with epilepsy (PWE). MethodA hospital-based cross-sectional study was conducted from April 20 to June 27/2019, through patient interviews and patient's chart review (medication and clinical information). Data were analyzed using SPSS version 20. The psychometric property was done using Cronbach's alpha test value of >0.7 as accepted internal consistency and Kaiser-Meyer-Olkin (KMO) measure of sample size adequacy value of �0.5 as acceptable construct validity, for Afaan Oromo version questionnaire. Multivariate linear logistic regression analysis was done to find predictors for the HRQOL score. ResultsOf 121 PWE included in the study, 24.4% had overall poor HRQOL with the overall mean ±SD score of 56.42±10.96. The predictors for low overall HRQOL score were: presence of co-morbidity (B = -5.620, SE = 1.531, p<0.0001, 95% C.I = -8.656 to -2.584), uncontrolled seizure for at least 2 years (B = -4.239, SE = 1.296, p = 0.001, 95% C.I = -6.809 to -1.670), divorced (B = -8.423, SE = 2.241, p<0.0001, 95%C.I = -12.867 to -3.978) relative to married, and no education (B = -8.715, SE = -8.15, SE = 2.604, p = 0.001, 95%C.I = -9.648 to -1.316) relative to who had level of education above tertiary. In addition, uncontrolled seizure (irrespective of time since seizure-free) (B = -10.083, SE = 2.104, p<0.0001, 95%C.I = -14.256 to -5.910), being widowed (B = -9.300, SE = 3.594, p = 0.011, 95%C.I = -16.429-2.170) relative to married and being illiterate/no education (B = -13.004, SE = 3.910, p = 0.001, 95%C.I = -20.760 to -5.248) relative to educational level of tertiary and above were found to PLOS ONE | https://doi.