BACKGROUND: Few studies are focused on the quality of life (QOL) of primary caregivers and the effects of the clinical variables of epilepsy and patient psychiatric comorbidity on primary caregivers. PURPOSE: Our main objective was to describe QOL and level of burden (LB) in caregivers of people with epilepsy (PWE) at a tertiary-care hospital in Mexico City. A secondary purpose was to determine if LB and QOL were different between caregivers of patients with neuropsychiatric comorbidity and caregivers of patients without neuropsychiatric comorbidity. METHODS: One hundred and fifty-one caregivers of PWE were assessed with the short version of the World Health Organization Quality of Life (WHOQOL) scale (WHOQOL-BREF) and the Zarit Burden Interview. Patients' clinical and demographic data, along with their psychiatric histories, were collected. RESULTS: One hundred and twelve patients had psychiatric comorbidity. The mean LB score of the caregivers was 26.25±16.28. The mean scores for the WHOQOL-BREF domains were as follows: physical health, 47.8±10.7; psychological health, 55.4±11.5; social relationships, 47.23±18.6; and environment, 48.7±11.6. The caregivers of patients with psychiatric comorbidity had lower scores in the domains of psychological health (p=0.034) and social relationships (p=0.029) compared with caregivers of PWE without comorbidity. On adjusted multivariate analysis, aggressiveness (p=0.008), age at onset of epilepsy (p=0.02), and years with epilepsy (p=0.01) were associated with higher caregiver LB scores; higher caregiver years of education were associated with better psychological health (p=0.002) and more years with epilepsy (p=0.03) with lower QOL scores. CONCLUSION: Aggressive behavior was the psychiatric comorbidity most clearly associated with lower QOL and higher LB. Longer duration of epilepsy was related to higher burden and lower QOL. More years of education of the caregiver were associated with better QOL. We found no significant correlation between seizure control and QOL or LB.