Abstract Background In adult research, neighborhood walkability has been acknowledged as an important construct among the built environmental correlates of physical activity. Research into this association has only recently been extended to adolescents and the current empirical evidence is not consistent. This study investigated whether neighborhood walkability and neighborhood socioeconomic status (SES) are associated with physical activity among Belgian adolescents and whether the association between neighborhood walkability and physical activity is moderated by neighborhood SES and gender. Methods In Ghent (Belgium), 32 neighborhoods were selected based on GIS-based walkability and SES derived from census data. In total, 637 adolescents (aged 13-15 year, 49.6% male) participated in the study. Physical activity was assessed using accelerometers and the Flemish Physical Activity Questionnaire. To analyze the associations between neighborhood walkability, neighborhood SES and individual physical activity, multivariate multi-level regression analyses were conducted. Results Only in low-SES neighborhoods, neighborhood walkability was positively associated with accelerometer-based moderate to vigorous physical activity and the average activity level expressed in counts/minute. For active transport to and from school, cycling for transport during leisure time and sport during leisure time no association with neighborhood walkability nor, with neighborhood SES was found. For walking for transport during leisure time a negative association with neighborhood SES was found. Gender did not moderate the associations of neighborhood walkability and SES with adolescent physical activity. Conclusions Neighborhood walkability was related to accelerometer-based physical activity only among adolescent boys and girls living in low-SES neighborhoods. The relation of built environment to adolescent physical activity may depend on the context.