In patients with end-stage renal disease, excessive blood flow through an arteriovenous fistula (AVF) may lead to volume overload-induced cardiac remodeling and heart failure. It is unclear which patients with hyperfunctional AVF may benefit from AVF reduction or ligation. The indication for the procedure is often based on AVF flow. Because cardiac remodeling is driven by increased venous return, which is equivalent to cardiac output, we hypothesized that an elevated cardiac index (CI) might better identify subjects with reverse remodeling after AVF reduction. Thirty patients (age 52±12 years, 73% male) with AVF flow ⩾1.5 l min(-1) underwent comprehensive echocardiographic evaluations before and after AVF reduction. At baseline, 16 patients had a normal CI (2.5-3.8 l min(-1) m(-2)) and 14 had a high CI (4.0-6.0 l min(-1) m(-2)). A left ventricular end-diastolic diameter decrease after operation was predicted by elevated baseline CI (P<0.01), but not elevated AVF flow (P=0.07). There was a significant decrease in CI, left ventricular mass, left atrial and right ventricular diameter and pulmonary systolic pressure in the high CI group but not in the normal CI group. After AVF reduction, systemic vascular resistance decreased in the normal CI group, whereas it did not change in the high CI group. In conclusion, reduction of high-flow AVF leads to reverse cardiac remodeling but only in patients with elevated CI. The variability of the response of systemic vascular resistance to AVF flow may explain this observation. Increased CI but not increased AVF flow may better determine candidates for AVF reduction.