The aim of the study was to explore the relationship between religious involvement (RI) and quality of life (QoL) in caregivers of patients with schizophrenia, while adjusting for key confounding factors such as socio-demographic and clinical characteristics. This study was conducted in the public mental health services in Bolivia, Peru and Chile. The data collected included RI, socio-demographic information, clinical characteristic of the patients and caregiver's QoL using the S-CGQoL questionnaire. A multivariate analysis using multiple linear regressions was performed to determine variables potentially associated with QoL levels. Two hundred and fifty-three patients with their caregivers participated in the study. Caregivers' RI was not significantly associated with overall QoL nor its individual components. The only exception was an unexpected modest inverse association between RI and one QoL dimension (psychological and physical well-being). In contrast, the following caregivers' socio-cultural and economic factors were significantly associated with low QoL level of caregivers: being a mother, identifying with Aymara ethnicity and having lower family income. Among patients, the clinical characteristics of being woman, younger, and having lower age of onset and more severe symptoms was associated with lower QoL. Our study found that socio-cultural, economic and clinical factors were associated with caregivers' QoL.