Higher levels of physical activity are associated with lower rates of coronary heart disease (CHD). Prior studies suggest this is partly due to lower levels of inflammation and insulin resistance. We sought to determine whether physical activity level was associated with inflammation or insulin resistance during a 5-year period in outpatients with known CHD. We evaluated 656 participants from the Heart and Soul Study, a prospective cohort study of outpatients with documented CHD. Self-reported physical activity frequency was assessed at baseline and after 5 years of follow-up. Participants were classified as low versus high activity at each visit, yielding 4 physical activity groups: stable low activity, decreasing activity (high at baseline to low at Year 5), increasing activity (low at baseline to high at Year 5), and stable high activity. We compared Year 5 markers of inflammation (C-reactive protein [CRP], interleukin-6, and fibrinogen) and insulin resistance (insulin, glucose, and A1c) across the 4 activity groups. After 5-years of follow-up, higher activity was associated with lower mean levels of all biomarkers. In the fully adjusted regression models CRP, interleukin-6, and glucose remained independently associated with physical activity frequency (log CRP p-trend across activity groups = 0.03; log interleukin-6 p-trend = 0.01; log glucose p-trend = 0.003). Individuals with Stable High Activity typically had the lowest levels of biomarkers. In conclusion, in this novel population of outpatients with known CHD followed for 5 years, higher physical activity frequency was independently associated with lower levels of CRP, interleukin-6, and glucose.