Background: Down syndrome (DS) is the most common chromosomal abnormality affecting numerous organs, including the orofacial region. The objective of the present study was to assess the prevalence of lip and oral soft tissue lesions, with particular emphasize on the incidence of fissured tongue, lip fissures and angular cheilitis, among individuals with DS in Yemen. Material and Methods: This controlled cross-sectional study included 50 children with DS (6-18 years), and 50 age- and gender-matched healthy controls. The prevalence of orofacial soft tissue lesions was evaluated in both groups. Data were analyzed by Chi-square and Fisher tests, and p <0.05 was considered to be statistically significant. Results: Ten orolabial lesions were identified among the subjects. The most frequently seen lesions were: Fissured tongue (78.0%), lip fissures (64.0%), angular cheilitis (38.0%) and Cheilitis (14.0%). The frequencies of these lesions were significantly higher in children with DS than healthy controls ( P < 0.001). Most of lip fissures were in the lower lip, and 80% of the fissures were in the midline. Conclusions: The prevalence of lip and oral lesions among individuals with DS is remarkably high. Hence, oral physicians should be more aware of the orofacial findings seen more frequently in this genetic disorder .