The balance between the angiostatic factor endostatin (ES) and angiogenic factor osteopontin (OPN) is essential in physiological and pathological angiogenesis. Several circumstances might influence this equilibrium and are of distinct interest when investigating mechanisms in coronary artery disease (CAD). The present explorative cross-sectional study was to investigate the influence of physical inactivity on ES and OPN levels in 181 male and 71 female patients with angiographycally verified CAD. Anamnestic and laboratory data were collected; ES was measured in serum and OPN in plasma by ELISA. Univariate analysis of variance was used to test for the influence of physical activity on ES and OPN levels and age, BMI, sex and diabetes status were included as covariates. ES and OPN intercorrelated significantly (r = 0.42; p < 0.001). ES and OPN decreased significantly in response to increasing activity level of patients suffering CAD (F = 5.5; p < 0.001 and F = 3.6; p < 0.01 resp.). This study is the first to show a linear decrease in ES and OPN levels in CAD patients depending on the degree of physical activity undergone. Lower levels of ES and OPN in physically active patients might be a sign of increased angiogenesis and decreased inflammation and calcifying activity and therefore contribute to the understanding of the damaging effect of physical inactivity in cardiovascular disease.