The aims of this study were to examine cross-sectional, and longitudinal association of different measures of obesity and physical fitness with cardiovascular disease (CVD) risk factors in adolescents with Down syndrome. Longitudinal analysis included 90 adolescents with Down syndrome. Obesity and physical fitness were measured following the ALPHA battery. Blood pressure and blood samplings (glucose, total cholesterol, high-density lipoprotein cholesterol, and serum lipid triglycerides levels (mg/dl) were determinated. In cross-sectional analyses, obesity was positively associated with single CVD risk factors and CVD risk factor index (all p <.05). In the prospective analyses, obesity was not associated with single CVD risk factors, but components of physical fitness at baseline impact in some single CVD risk factors (all p <.05). Obesity might be more strongly related to current cardiovascular-health, while components of physical fitness might be more related to future cardiovascular-health in adolescents with Down syndrome. [ABSTRACT FROM AUTHOR]