The need to enhance the echocardiographic determination of left ventricular ejection fraction (LVEF) is greatest in patients with suboptimal images. We have previously demonstrated that in difficult-to-image patients, contrast-enhanced power harmonic imaging resulted in accurate calculation of LVEF by using Simpson's method. However, the incremental accuracy of contrast enhancement with other methods of determining LVEF has not been examined. This study prospectively assessed the comparative accuracy of LVEF determination by using the Quinones' method with fundamental imaging (FU), tissue harmonic imaging (TH), contrast-enhanced harmonic imaging [TH(CON)], as well as Quinones' method with contrast-enhanced power harmonic imaging [POW(QUIN)] in 62 patients with suboptimal images. LVEF was also calculated by using contrast-enhanced power harmonic imaging and Simpson's method [POW(SIMP)] in these patients. We demonstrated that LVEF calculated from the POW(QUIN) mode had the best agreement with radionuclide angiography (standard of comparison) compared with FU, TH, and TH(CON). However, POW(SIMP) was even more accurate. In conclusion, when the Quinones' method was used to calculate LVEF in difficult-to-image patients, POW(QUIN) mode was the most accurate. However, POW(SIMP) was even more accurate and should be the method of choice when a high degree of quantitative accuracy is required.