© 2019 The Author(s). Background: The impact of looking after children who live with complex chronic conditions is a growing public health issue. However, it is unclear whether sociodemographic and psychosocial variables can be used to predict the burden on the caregiver and how the profiles of families of children with chronic diseases are defined and structured. The objective of this study was to identify multivariate sociodemographic and psychosocial variables as well as sociocultural and familial factors to analyze the caregiver burden of family caregivers of children with chronic diseases. Methods: A cross-sectional study was conducted involving 416 family caregivers of children with chronic diseases at the National Institute of Health in Mexico City. The participants responded to a questionnaire on sociodemographic variables and a battery of 7 instruments that examined caregiver burden, family support, parental stress, anxiety, support networks, family functioning, historic-psycho-socio-cultural premises and the World Health Organization Well-Being Index. Results: A multivariate analysis using hierarchical multiple regression models showed that the variables included in the psychosocial and sociodemographic profile as a whole explained 40% of the variance in caregiver burden, taking sociocultural historical premises, stressors and anxiety into account as positive individual predictors. Negative individual predictors for caregiver burden included upper secondary education, social support networks, family support, family functioning and well-being. The sociodemographic profiles of family caregivers were as follows: female (81.7%); mean age, 31.7 years (standard deviation [SD], 8 years); married (79.3%); nuclear family (60%); basic education (62.7%); unpaid work (66.3%); and a daily household income of approximately 4 USD (61.1%). Conclusions: The caregiver burden of family caregivers of children with chronic diseases is defined and structured based on personal, family, and sociocultural factors. These features provide evidence to conduct research and implement intervention strategies with regard to families facing adversity, risk and vulnerability during a child's disease.