Increased mitral valve E point to ventricular septal separation (EPSS) is widely used as an echocardiographic index of depressed left ventricular (LV) ejection fraction (EF), yet LV size has not been examined as an independent variable potentially affecting EPSS. Accordingly, we studied end-diastolic dimensions (EDD). Twenty normal controls had EPSS 3.2 +/- 2.2 mm (mean +/- SD), EDD 47 +/- 5 mm, EPSS/EDD ("normalized" EPSS) 0.07 +/- 0.04, and fractional shortening (FS%) 38 +/- 6%. Nine patients with pure chronic mitral regurgitation had dilated LV (EDD = 65 +/- 7 mm) with normal LV function (FS% 41 +/- 5%; angiographic EF 62 +/- 9%); eight patients had dilated cardiomyopathy (EDD 69 +/- 8 mm) with decreased LV function (FS% 16 +/- 7%; angiographic EF 32 +/- 8%); and eight patients with amyloid cardiomyopathy had nondilated LV (EDD 42 +/- 5 mm) with decreased LV function (FS% 19 +/- 6; angiographic EF 35 +/- 7%). Mitral E point to ventricular septal separation and EPSS/EDD accurately separated individuals with normal and abnormal LV function irrespective of LV size (chi 2 = 36.7; p less than 0.00001). Increased internal dimensions per se did not affect EPSS unless depressed LV function coexisted. EPSS is therefore a valid predictor of depressed ejection phase indices independent of LV size.