This study aimed to describe the 5-yr longitudinal change in moderate-to-vigorous physical activity (MVPA) among urban adolescents in Ho Chi Minh City, Vietnam, and to identify individual, family, and environmental factors associated with changes in MVPA. The Ho Chi Minh City Youth Cohort is a 5-yr longitudinal cohort with systematic random sampling of 759 students (48% boys) from 18 junior high schools in Ho Chi Minh City, conducted from 2004 to 2009. All measures were taken on five separate occassions. MVPA was assessed by self-report and accelerometry. Data were analyzed using multilevel linear regression models with estimation by generalized linear latent and mixed models. Overall, after adjusting for covariates, students' accelerometer-based MVPA reduced 38% per annum (rate ratio = 0.62, 95% confidence interval (CI) = 0.59-0.64). Boys spent 2.9 times more in MVPA (rate ratio = 2.94, 95% CI = 2.63-3.22) than their female peers. Compared with normal-weight adolescents, overweight and obese adolescents were doing 40% (rate ratio = 0.60, 95% CI = 0.53, 0.67) less MVPA. MVPA significantly declined among Vietnamese adolescents with age. This finding is similar to those reported among Western adolescents and suggests that strategies to promote physical activity in adolescents are a priority in Vietnam because economic transitioning potentially increases the risk of adopting unhealthy lifestyle behaviors associated with obesity and chronic diseases.