To evaluate the relationship between cardiorespiratory fitness (CRF), expressed as maximal oxygen uptake (ml.kg-1.min-1), metabolic syndrome (MetS), and high-sensitivity C-reactive protein (hs-CRP), a marker of systemic inflammation. The relationship between CRF, MetS, and hs-CRP was examined in a cohort of 173 men and women. CRF was evaluated using a Bruce protocol treadmill test and measured as estimated maximal oxygen uptake (VO2 max). Participants' physical activity status was self-reported. Plasma hs-CRP levels were measured using a standardized immunoassay, and the diagnostic criteria for MetS were based on guidelines established by the International Diabetes Federation (IDF). An inverse association was observed between hs-CRP levels and estimated VO2 max (p<0.01). Additionally, hs-CRP increased linearly with the number of MetS criteria present (p<0.01), while the estimated VO2 max decreased as the number of MetS criteria increased (p<0.01). Moreover, higher estimated VO2 max correlated with increased self-reported physical activity levels (p<0.01). Notably, participants engaging in two to three hours of exercise per week had hs-CRP levels ≤2.5 mg/L (p=0.018), considered a low-to-moderate risk range. Higher CRF, reflected by an estimated VO2 max, ≥45 ml/kg/min, is associated with lower hs-CRP levels and fewer MetS criteria. Additionally, regular physical activity, corresponding to higher VO2 max, appears to reduce systemic inflammation and ameliorate MetS risk factors. These findings support the mechanisms by which improved CRF and exercise may lower the risk of cardiovascular diseases (CVD) and type 2 diabetes (T2DM).