Background: In hemodialysis patients, left ventricular hypertrophy (LVH) correlates with mortality. The reason for LVH in uremics is multifactorial. The primary objective of our study was to investigate the effects of a multi-interventional treatment strategy on LVH. Methods: In 230 ambulatory patients, including patients with coronary artery disease, diabetes, diastolic and systolic dysfunction, we continued optimized cardiac therapy (β-blockers, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) with full anemia correction by intravenous epoetin-β. The dose of epoetin-β for maintaining target hemoglobin (Hb) was 68 ± 23 IU/kg/week. Serial echocardiograms were recorded every 3–6 months. The mean observation period was 4.8 ± 1.2 years. Results: Mean Hb at baseline was 11.2 ± 2.0 versus 14.1 ± 1.4 g/dl (p < 0.001) at study end. There was a significant reduction in left ventricular mass index (LVMI: 159 ± 50.4 vs. 130.2 ± 42.7 g/m<sup>2</sup>; p < 0.001). In a subgroup of 2/3 of the patients, LVMI returned to normal (169 ± 33 vs. 114 ± 14 g/m<sup>2</sup>; p < 0.001). Conclusion: Baseline LVMI (p < 0.001), Hb increase (p < 0.03), and triple cardiac therapy (p < 0.03) were significant and independent prognostic factors for a reduction in LVMI. The annual cardiovascular mortality was 5%. Even anemia correction from 12 to 14 g/dl results in further (p < 0.001) regression of LVMI.