Background: This study aimed to assess the influence of various clinical factors on the quality of life perception of patients with epilepsy over a follow-up period in current clinical practice. Methods: Thirty-five PWE evaluated via video-electro-encephalography in the Clinical Hospital of Psychiatry and Neurology in Brasov, Romania, were included, and the quality of life was assessed using the Romanian version of the QOLIE-31-P questionnaire. Results: At baseline, the mean age was 40.03 (±14.63) years; the mean duration of epilepsy was 11.46 (±12.90) years; the mean age at the first seizure was 28.57 (±18.72); and the mean duration between evaluations was 23.46 (±7.54) months. The mean (SD) QOLIE-31-P total score at the initial visit (68.54 ±15.89) was lower than the mean (SD) QOLIE-31-P total score at the follow-up (74.15 ± 17.09). Patients with epileptiform activity recorded via video-electro-encephalography, using polytherapy, those with uncontrolled seizures, and those with one or more seizures per month had statistically significantly lower QOLIE-31-P total scores at baseline and follow-up. Multiple linear regression analyses revealed seizure frequency as a significant inverse predictor of quality of life in both evaluations. Conclusions: The QOLIE-31-P total score was improved during the follow-up period, and medical professionals should use instruments to evaluate quality of life and identify patterns while trying to improve the outcomes of patients with epilepsy.