Abstract Background: Metabolic syndrome (MetS) is a systemic inflammatory state. Low physical activity (PA) could modify this patho-physiology or act as an independent contributor to inflammation. Previous studies of both conditions have identified altered levels of inflammation- and immune-related proteins based on limited sets of candidate markers. Methods: We investigated associations of MetS and low PA with circulating inflammation markers in a stratified random sample of Japanese adults (N = 774, mean age 60.7 years) within the Japan Public Health Center-based Prospective Study (JPHC) Cohort II. AHA/NHLBI criteria were used to define MetS (19%) and the bottom quartile of PA was considered low. 110 circulating biomarkers, including cytokines, chemokines, and soluble receptors were measured by multiplex bead-based and proximity-extension assays. Associations of MetS and low PA with marker quantiles were adjusted for each other and for age, sex, study site, cigarette smoking, alcohol consumption, and blood sample fasting state by ordinal logistic regression. P values were corrected for FDR. Results: MetS was significantly associated with levels of six markers: IL18R1 [odds ratio 2.37; 95% confidence interval (CI), 1.45–3.87], CRP (2.07; 95% CI, 1.48–2.90), SAP (2.08; 95% CI, 1.47–2.95), CCL19/MIP3β (2.06; 95% CI, 1.48–2.88), CXCL12/SDF1α+β (0.48; 95% CI, 0.32–0.65), and CCL28 (0.44; 95% CI, 0.27–0.71). Low PA had no significant marker associations. Conclusions: Positively associated markers with MetS are mostly Th1 immune response–related and acute phase proteins, whereas negatively associated markers are generally Th2-related. Impact: MetS is associated with a broad range of alterations in immune and inflammatory biomarkers that may contribute to risks of various chronic diseases, independent of low PA.