Coronary artery collaterals may have a protective role against myocardial ischemia at rest. However, their role during stress is controversial and poorly defined. We evaluated 212 consecutive patients (57 +/- 16 years; 70% men) who underwent coronary angiography and stress echocardiography within a 3-month period. This cohort of patients (all had significant epicardial coronary artery disease) was divided into 3 groups based on the presence and type of collaterals: group A, no collaterals; group B, collaterals supplied by vessels without flow-limiting stenosis; and group C, collaterals supplied by vessels with flow-limiting stenosis. In all patients, angiographic jeopardy score, ejection fraction, and regional and cumulative wall motion score indexes (WMSIs) at rest and during stress were evaluated. Angiographic jeopardy scores were 2.9, 3.5, and 7.3 for groups A, B, and C, respectively. Baseline ejection fraction was similar between groups A and B (48% vs 46%, p = NS) but lower in group C (31%, p <0.01). During stress echocardiography, all groups demonstrated a significant increase in WMSI from baseline (WMSI at rest vs that during stress 1.72 +/- 0.06 vs 1.79 +/- 0.04 for group A, 1.97 +/- 0.06 vs 2.09 +/- 0.03 for group B, 2.35 +/- 0.11 vs 2.41 +/- 0.07 for group C; p <0.01 for all groups). In addition, the number of ischemic segments increased significantly in all groups (2.96 +/- 0.07 in group A vs 4.52 +/- 0.11 in group B vs 5.61 +/- 0.13 in group C, p <0.01). Coronary artery collaterals do not offer protection against stress-induced myocardial ischemia. Moreover, the presence of jeopardized angiographic coronary collaterals (group C) is associated with a higher angiographic jeopardy score, higher baseline WMSI, and decreased ejection fraction.