Abstract Background: Approximately half of all Down syndrome (DS) infants have a congenital heart defect (CHD), including atrioventricular septal defects (AVSD), atrial septal defect (ASD), ventricular septal defect (VSD) and tetralogy of Fallot (ToF). Aim of Study: The study aimed to determine the prevalence, cardiovascular phenotypes, and gender differences in CHD associated with DS in Alexandria, Egypt. Patients and Methods: The present study is a retrospective descriptive single-centre study included 722 DS patients attending the Human Genetics clinic, Medical Research Institute, Alexandria University. Data were retrieved from the medical files of DS patients. Results: CHD was present in 59% of DS patients. The most common were ASD (42.3%) and AVSD (25.1%). CHDs were more frequent in females, including total CHDs (p=0.03, OR: 1.393), ASD (p=0.043, OR: 1.417), AVSD (p=0.034, OR: 1.56), and severe CHDs (p=0.024, OR: 1.544). Conclusion: CHDs are more prevalent in female DS patients. Gender differences may imply a role of sex in the association between CHD and DS.