Two widely used methods for left ventricular (LV) ejection fraction (EF) determination, echocardiography (echo) and gated single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI), often have wide limits of agreement. Factors influencing discrepancies between core laboratory echo and MPI LVEF determinations were examined in a large series of heart failure (HF) subjects and normal controls. 879 HF and 101 control subjects had core lab analyses of echo and MPI (mean time between procedures 7-8 days). LVEF differences were analyzed using one-way analysis of variance and Bland-Altman plots. Relationships between LVEF differences and patient characteristics and outcome endpoints (mortality and arrhythmias) were explored with logistic regression, Cox proportional hazards models, and Kaplan-Meier survival analyses. There was a systematic difference between the 2 modalities; echo LVEF was higher with more severe LV dysfunction, MPI LVEF higher when systolic function was normal. LVEF results were within ±5% in only 37% of HF and 23% of control subjects. Considering discordance around the LVEF threshold 35%, there was disagreement between the 2 methods in 305 HF subjects (35%). Male gender (odds ratio (OR) = 0.200), atrial fibrillation (OR = 2.314), higher body mass index (OR = 1.051) and lower LV end-diastolic volume (OR = 0.985) were the strongest predictors of methodologic discordance. Cardiac event rates were highest if both LVEF values were ≤35% and lowest when both LVEF values were >35%. In conclusion, substantial disagreements between LVEF results by echo and MPI are common. HF patients with LVEF ≤35% by both techniques have the highest 2-year event risk.