Background: Down syndrome (DS) is the most common chromosomal abnormality encountered by primary care physicians. The demands of families with DS children are significantly high with possible burdens on their primary caregivers.Objective: To assess the burden of DS children on their family primary caregivers and to identify the variables associated with caregiver burden.Methods: A cross-sectional study was conducted in Mansoura, Egypt from March 2019 to March 2020 including 457 family primary caregivers and their DS children. Socio-demographic and clinical data were collected through direct interviews. Caregiver burden was assessed by Zarit Burden Interview (ZBI-22) scale. The associations between categorical variables were tested using chi-square test, crude odds ratio and 95% confidence interval. Logistic regression analysis was carried out to detect the variables independently associated with caregiver burden.Results: More than half (51.9%) of caregivers had no or little burden, 40.7% had mild to moderate burden and 7.4% had moderate to severe burden. Female caregiving, single parent status and DS children of age less than 6 years old, female gender and having congenital heart diseases were the variables independently associated with mild to severe burden with adjusted odds ratios of 4.2, 2.5, 1.5, 2.1 and 1.7, respectively.Conclusions: Less than half of family primary caregivers of DS children in Mansoura, Egypt suffered from mild to severe burden. Primary care physicians could recognize caregivers at risk of burden using ZBI-22 scale, and provide appropriate social, medical and psychological care for parents and DS children to mitigate this burden. [ABSTRACT FROM AUTHOR]