Systemic low-grade inflammation (SLGI) is an intermediary common condition to the physiopathology of chronic noncommunicable diseases and targeting its determinants could lead to more efficient public health strategies. We aimed to investigate SLGI-independent associations with lifestyle, diet, and genetic factors in a population-based sample of adults using a systemic low-grade inflammation score (SIS).The study sample is composed of 269 participants from the cross-sectional population-based Health Survey of Sao Paulo (2008-2010), ages 20 to 59 y, whose data on socioeconomic variables, lifestyle, health parameters, and blood samples were available. Diet was assessed by two 24-h recalls, and the Brazilian Health Eating Index-Revised (BHEI-R) was scored. From blood samples, 30 single nucleotide polymorphisms on inflammatory genes were genotyped, and plasma eleven inflammatory biomarkers levels that composed the SIS were determined. A multiple, stepwise, linear regression was used to investigate SIS-independent associated factors.Factors independently associated with SIS were BHEI-R score (partial R² = 5.1; β = -0.13; P = 0.003), body mass index (partial R² = 3.4; β = 0.19; P = 0.001), TLR4 rs5030728 GA + AA genotype (partial R² = 3.1; β = -1.37; P = 0.008), age 50 to 59 y (partial R² = 2.5; β = 1.93; P = 0.029) in comparison with the reference category (20 to 29 y), and commuting physical activity >150 min/wk (partial R² = 2.2; β = -1.29; P = 0.043) after adjustment for current smoking status, medication use, and dietary misreporting.Eating a lower quality diet, having a higher body mass index score and age, being GG homozygous for TLR4 rs5030728, and spending <150 min/wk in transportation physical activity are independent determinants of SLGI.