Background: Transcultural studies regarding the comparison of levels of burden in caregivers of patients with Alzheimer's disease (AD) from Europe and Latin America are rare. We designed this study to investigate the differentiating factors associated with burden in Brazilian and Spanish caregivers of patients with AD. Methods: This is a cross-sectional study composed by samples of outpatients with AD and their caregivers from Brazil (n = 128) and Spain (n = 146). Caregivers answered the Zarit Burden Interview (ZBI) and a Sociodemographic Questionnaire. Patients were assessed with the Mini-Mental State Examination (MMSE), Functional Activities Questionnaire (FAQ), Disability Assessment for Dementia (DAD), Neuropsychiatric Inventory (NPI), and Clinical Dementia Rating (CDR) Scale. Results: In the multivariate regression analysis, high burden levels were reported in Brazil, when caregivers were female (p = 0.025) and when patients did not attend Day Care Center (p = 0.025). In Spain, high burden levels were associated with living with the patient (p = 0.014), younger caregivers (p = 0.003), and participation of patients at Day Care Center (p = 0.046). Also, different neuropsychiatric symptoms explained high burden levels: in Brazil, depression (p < 0.001) and anxiety (p = 0.024) and, in Spain, apathy/indifference (p < 0.001), agitation/aggression (p = 0.019) and irritability/lability (p = 0.027). Conclusions: Caregivers' gender, patients who attendedDay Care Center and neuropsychiatric symptoms were differentiating factors in the burden of Brazilian and Spanish caregivers