Depression is a major mental health problem during adolescence. This study, using a sample of Chinese adolescents, examined the separate and combined effects of perceived school-related stress and of family socioeconomic status (SES) on the prevalence of depressive symptoms. A total of 1774 Chinese students from Grades 7-12 were recruited into our questionnaire survey. School-related stress was measured by the Effort-Reward Imbalance Questionnaire-School Version, family SES was assessed by a standardized question, and depressive symptoms were evaluated by the Center for Epidemiological Studies Depression Scale for Children. Multivariate logistic regression was applied, adjusting for age, gender, grade, smoking, alcohol drinking and physical activity. It was found that high school-related stress and low family SES were associated with elevated odds of depressive symptoms, respectively. The effect of school-related stress was particularly strong in low SES group. In adolescents with both high stress at school and low SES, the odds ratio was 9.18 (95% confidence interval = 6.53-12.89) compared to the reference group (low stress at school and high SES). A significant synergistic interaction effect was observed (synergy index = 2.28, 95% confidence interval = 1.56-3.32). The findings indicated that perceived school-related stress, in terms of effort-reward imbalance, was related to depressive symptoms in this sample of Chinese adolescents. The strong interaction with family SES suggests that health promoting efforts in school settings should be targeted specifically at these socially deprived groups.