Schistosomiasis due to infection with Schistosoma mansoniis a public health problem in both tropical and sub tropical countries. Thus, effective control of the disease requires determining its prevalence rate, identifying risk factors of infection and high-risk groups. Therefore, the objective of this study was to establish the prevalence of S. mansoni infection and associated risk factors among schoolchildren in suburbs of Mekelle city, Tigray, Northern Ethiopia. For this purpose, a cross-sectional parasitological examination wasconducted on457 schoolchildren from November, 2010 to March, 2011. Stool samples were collected and examined by the Kato-Katz technique. Semi-structurered interview questionnaire were administered to the study subjectsto identify possible risk factors of infection with S. mansoni. Furthermore, malacological survey was conducted to check the presence of snail intermediate hosts of S. mansoni in the study area. The overall prevalence of S. mansoni in the schoolchildren was 23.9 %. Higher prevalence was detected in male children (30.71%) than in females (14.12 %) (χ 2 = 16.642, P = 0.000). On the other hand, the highest (31.2%) prevalence was recorded in children with ages ranging from 10 - 14 years followed by thoseaged 5 - 9 (11.4 %) and 15 - 19 (9.8 %) years (χ 2 = 23.865, P = 0.000), respectively. This study revealed the association of S. mansoni infection with older age groups, 10 -14 years (OR = 0.114, P = 0.001), time of residence in the study area (OR = 0.462, P = 0.011), water source (OR = 0.371, P = 0.020), previous history of schistosomiasis treatment (OR = 0.246, P = 0.000), frequency of water contact (OR = 26.958, P = 0.004), crossing water bodies (OR = 3.049, P = 0.001), working in an irrigated agricultural field (OR = 7.363, P = 0.000) and distance of home from water bodies (OR = 5.163, P = 0.000). Moreover, this study determined the presence of snail intermediate hosts of S. mansoni in the study areas . Hence, the study areas are considered important epidemiological foci for the transmission of S. mansoni. Therefore, it is necessary to undergo wide scalesurveillance and institute proper control and prevention strategies against infection with Schistosoma mansoni