Background: Ejection fraction (EF) by echocardiography (echo) is the recommended screening modality for treatment-related cardiac dysfunction in survivors of childhood cancer. Because decreased EF occurs late in its natural history more sensitive detection methods are needed. We hypothesized that myocardial strain would improve identification of survivors with reduced exercise capacity. Methods: Analysis included 1,107 >10 yr survivors of childhood cancer (median age 32 yrs, range 18-59; 593 anthracycline-no chest radiation [RT], 206 chest RT-no anthracycline, and 308 anthracycline + chest RT). Echo included systolic (3D EF, abnormal defined as <50%) and diastolic function (grades 1-3 abnormal), and global longitudinal (>-18.9) and circumferential (>-22.1) myocardial strain. Exercise capacity was assessed with a 6-minute walk (<490 meters abnormal). Associations between echo measures and exercise capacity were assessed using logistic regression adjusted for age, weight, height, pulmonary function, muscle strength, diastolic function, hypertension and diabetes to calculate odds ratios (ORs) and 95% confidence intervals (CI). Results: Systolic dysfunction was detected in 5%, diastolic dysfunction in 12%, and abnormal longitudinal and circumferential strain in 47% and 57%. Longitudinal strain was the only echo measure associated with reduced exercise capacity (OR 1.7, CI 1.1-2.6) with no association for 3D EF (OR 0.6, CI 0.2-1.8), diastolic function (OR 1.1, CI 0.6-1.9), or circumferential strain (OR 1.0, CI 0.7-1.6). Abnormal longitudinal strain was associated with older age, male sex and dose of chest RT. Among survivors with normal EF, abnormal longitudinal strain was significantly associated with detection of survivors with reduced exercise capacity (OR 1.7, CI 1.0-2.7). Conclusions: Among adult survivors of childhood cancer, abnormal global longitudinal strain is prevalent, associated with chest-directed RT exposure, and is the only echo measure independently associated with reduced exercise capacity. Longitudinal strain identifies at-risk survivors who should be targeted for potential clinical interventions.