BACKGROUND: Cardiovascular disease (CVD) and depression are bidirectionally associated in adults. However, the direction of association between CVD risk and depressive symptoms in young people and potential mechanisms are poorly understood. METHODS: Using longitudinal birth cohort data, we created a CVD risk score age at 15 using age, ethnicity, physical activity, maternal social status, maternal smoking, own smoking, BMI, systolic blood pressure, LDL, HDL and triglycerides. We used regression analysis to test: (1) association between CVD risk score at age 15 and depressive symptoms at ages 12 and 18; (2) association of IL-6 and CRP at age 9 with depressive symptoms at age 12 and CVD risk score at age 15; and (3) mediating effects of CVD risk score on associations of IL-6/CRP at age 9 with depressive symptoms at age 18. RESULTS: The risk set comprised 5007 participants. CVD risk score in mid-adolescence was associated with depressive symptoms in early-adulthood (adjusted beta=0.06; standard error (SE)=0.02; p<0.001). Depressive symptoms in childhood were not associated with CVD risk score in mid-adolescence (adjusted beta=0.03; SE=0.02; p=0.11). Childhood inflammatory markers were associated with CVD risk score in mid-adolescence. Adolescent CVD risk score mediated the associations between childhood inflammatory markers and depressive symptoms in early-adulthood. LIMITATIONS: The cohort primarily comprises White individuals, limiting generalisability. Sample attrition required imputation for missing data. CONCLUSIONS: Association between CVD risk and depression in childhood/adolescence is unidirectional, with higher CVD risk increasing the risk of depressive symptoms. Childhood inflammation may increase risk of depression by influencing adolescent CVD risk.