Introduction: The mechanisms by which cardiovascular regenerative capacity, estimated as circulating levels of progenitor cell (CPC) counts, protect against adverse cardiovascular events remain unclear. Hypothesis: Circulating progenitor cells possess immune-modulatory properties and are hypothesized to mitigate inflammation that is characteristic of patients with CAD. We hypothesized that patients with fewer CPC will have higher inflammatory markers and worse outcomes. Methods: Patients with stable CAD were enrolled in a prospective study enumerating CPCs as CD34-expressing mononuclear cells (CD34+), and inflammation as levels of interleukin-6 (IL-6). Patients were followed for 5 years for the endpoints of death and myocardial infarction (primary) with repeat inflammatory biomarkers measured after a median of 2 years. The association between CPCs and change in IL-6 levels over time was determined using linear regression after adjustment demographic and clinical risk factors. Cox hazard models were used for time-to-event analyses after adjustment. Results: In the entire cohort of 392 patients, IL-6 remained unchanged (0.3 ± 2.4 pg/mL, p=0.45) after 2 years. CPC counts (log-transformed) were inversely correlated with the change in IL-6 levels (r=- 0.17, P <0.001). Thus, IL-6 declined by - 0.59 ((95%CI), -0.90, -0.20) pg/mL per 1 log higher CPC counts after adjustment for the demographic and clinical variables as well as medications. Using Cox hazard models adjusted for these risk factors, a rise in 1 pg/mL of IL-6 was associated with a 11% (95%CI, 9, 13) greater risk of death/MI. Low CPC counts were associated with a higher risk of death/MI (HR=1.7 (95%CI, 1.1-2.6). Using mediation analysis, we found that the change in IL6 level partly (by 40%) mediated the higher risk of adverse events among those with low CPC counts. Conclusions: Reduced cardiovascular regenerative capacity, measured as low circulating CPC levels, is independently associated with progressive inflammation in patients with CAD, which in turn is associated with poor outcomes. These findings support the role of endogenous regenerative capacity in passivating systemic inflammation and is a potential mechanism underlying its protective effects.