Background Left ventricular opacification (LVO) improves image quality at stress echocardiography (SE). We examined whether routine use of LVO adds incremental benefit and is cost-effective for diagnosis of coronary artery disease (CAD). Methods Contrast pharmacologic and/or exercise SE was performed in 135 patients (81 men; 56 ± 10 years) undergoing coronary angiography. Observers sequentially interpreted first standard, then LVO images; a positive SE was defined by resting or inducible wall motion abnormality in ≥2 segments. Coronary artery disease (75 patients, 119 territories) was defined as >50% stenosis. Three cost-effectiveness models were studied, and a sensitivity analysis was performed. Results Left ventricular opacification increased the sensitivity of SE (80%-91%; P = .03), including single-vessel CAD (65%-87%; P = .04), with no significant change in specificity (72%-77%; P = NS). Left ventricular opacification was of benefit to 14% of patients, unrelated to resting image quality. Use of LVO in all patients added 59% to the cost of the procedure ( P < .001), at a cost of $1069 per additional correct diagnosis. In a cost-effectiveness model based on cardiac outcomes after SE, LVO resulted in an increase in total cost of $1069. A 3.7% improvement in sensitivity resulted in a negative cost to identify CAD, but even 15% to 20% improvements in specificity failed to balance the cost of contrast for exclusion of CAD. Conclusions Left ventricular opacification adds significant incremental diagnostic benefit to standard SE, especially single-vessel CAD. Despite improved sensitivity, the use of contrast in all patients was not cost-effective when analyzed with a model based on previously published patient outcomes.