Background: Caregivers of patients with advanced cancer often face significant physical, social, and emotional distress. In many Latin American cultures, family plays a particularly important role in the decision-making process of patients with cancer, and relatives often assume the role of unpaid caregivers. However, there is limited research about the burden associated with cancer unpaid caregiving among patients living in Latin America. We aimed to describe the profile of caregivers and to identify patient-related factors associated with caregiver burden in a third-level cancer center in Mexico City. Methods: We conducted a cross-sectional analysis of baseline data from patients with advanced cancer and their caregivers included in a multidisciplinary patient navigator-led supportive care program in Mexico City (Te Acompañamos). At the time of enrollment in the program, caregivers completed a short version of the Zarit Burden scale and patients completed a series of screening questionnaires including assessments of quality of life (FACT-G), depression (PHQ-9), and anxiety (GAD-7). Life expectancy was calculated using the palliative performance scale (PPS). We used descriptive statistics, chi-square tests, and multivariate logistic regression analyses to understand which patient factors were associated with higher caregiver burden. Results: A total of 321 patients with advanced cancer (58% women; average age 63.3 +/- 14 years; 32.7 with hepatopancreatobiliary tumors) and 321 caregivers (67.1% women; 44% were the patient’s son/daughter; 29% were their spouses) were included. Sixty-four caregivers (20%) had a high caregiver burden (score > 16 in the Zarit scale). Caregiver burden was more common among the patients’ spouses (24.1 %) followed by brothers/sisters (23.6%). On univariate analysis, moderate/severe levels of depression (p = 0.001), moderate/severe levels of anxiety (p = 0.02), and lower PPS scores (p = 0.002) were associated with a high caregiver´s burden. Multivariate analysis showed that only PPS < 180 days was associated with increased odds of having caregiver burden (2.0; 95% CI 1.8-3.7); p = 0.02). Conclusions: A significant proportion of unpaid caregivers of Mexican patients with advanced cancer report high levels of caregiver burden, and the odds of having caregiver burden are increased when the patient has a calculated life expectancy of <6 months. These results suggest targets for future supportive care interventions to improve caregiver wellbeing in Latin American and Hispanic populations.