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A detrimental role of saturated fatty acids (SFA) on blood lipids has been suggested but not confirmed in adolescents. Physical activity (PA) may influence blood lipids by altering the metabolic fate of nutrients. To understand the integrated role of these lifestyle factors we tested the association of SFA intake with blood lipids in 15-year-olds, considering interactions with different PA levels.Children from the GINIplus and LISA cohorts with data on SFA, PA and blood lipids at age 15 years were included (n=830). SFA intake (% of total kcal) was estimated from food frequency questionnaires. PA (average min/day) was measured over one week by accelerometers and classified into sedentary, lifestyle (LSPA), or moderate-to-vigorous (MVPA). Blood lipids (total cholesterol, LDL, HDL, and triglycerides) were measured in serum and those with skewed distribution were log-transformed (all except HDL). Sex-stratified associations between SFA and blood lipids were assessed by linear regression, adjusting for potential confounders. Interaction terms were included between SFA and PA levels, and for significant interactions analyses were performed stratified by tertiles of the relevant PA level.No significant association was observed between dietary SFA and any of the blood lipid outcomes. Interactions were observed with time spent sedentary for the outcomes total cholesterol and HDL in females, and with time spent in LSPA for LDL and triglycerides, in males and females, respectively (p<0.1). Stratified analyses indicated a significant inverse association between SFA (per interquartile increase) and triglycerides in females, only in the lowest LSPA tertile (means ratio: 0.91 (95% confidence interval: 0.85; 0.98), p=0.01). Further, a significant positive association was observed with total cholesterol and LDL in males in the middle tertile of LSPA (1.08 (1.03; 1.14), p=0.004; and 1.12 (1.03; 1.21), p=0.01, respectively).Our findings do not indicate a significant association between SFA intake and blood lipids among adolescents. The role of dietary SFA on the lipid profile might vary in an activity-specific manner, although interpretation may be complicated due to non-intended noise arising from methodological limitations. For further insight, future analyses might consider other, possibly correlated nutrients.