BACKGROUND: Although cardiovascular events in hemodialysis (HD) patients are the most frequent on the day after a long (2 days) interdialytic interval (IDT), it has been uncertain whether accumulation or elimination of large extracellular fluid volume, electrolyte, and/or uremic substances is the culprit for this. We sought to test our hypothesis that the long IDT alters echocardiographic parameters at rest and during exercise in stable maintenance HD patients compared with other IDTs. METHODS: We performed a cross-sectional comparison using 1-way repeated analysis of variance or Friedman test of echocardiograms at 3 different IDTs, just after HD, after short IDT (1 day), and after long IDT, among 80 stable Japanese outpatients (age 61 ± 9 years, 60 males) on thrice weekly maintenance. End-systolic elastance (Ees), arterial elastance (Ea), and pressure-volume area (PVA) were estimated using a noninvasive single-beat technique. Ventricular-arterial coupling was assessed by Ea/Ees ratio. Measurements were repeated after 2-minute handgrip stress to evaluate cardiac reserve. RESULTS: Resting left ventricular end-diastolic volume index and stroke volume index were significantly larger after a 1-day IDT compared with just after HD and even more after a 2-day IDT. Although Ees, Ea, and Ea/Ees ratio at rest remained similar between short and long intervals, stroke work (SW) and PVA were higher after the long interval. During handgrip stress, a significant increase in Ea without corresponding rise in Ees was observed only after long IDT, resulting in decreased stroke volume index, SW, and SW/PVA efficiency. CONCLUSIONS: In a selective Japanese outpatient population on maintenance HD, there were no differences in resting cardiovascular function measured by echocardiography at 3 different IDTs. However, exercise-induced afterload mismatch assessed by the changes in Ea, SV, SW, and SW/PVA efficiency was most pronounced in individuals after the long IDT compared with other IDTs. Our findings report potential pathophysiologic echocardiographic parameters that attempt to explain why cardiovascular events are highest on the day after the long IDT compared to other IDTs in dialysis patients.