The functional role of regulatory T-cells (Tregs) in chronic heart failure (HF) is unknown. Using flow cytometry, we assessed Tregs during the progression of ischemic HF in male C57Bl/6 mice after coronary ligation and myocardial infarction (MI). At 7 d post-MI, circulating Tregs (% CD4+ T-cells) were comparable to sham-operated mice. Thereafter, blood Tregs significantly (p < 0.05 vs sham) increased ~1.5 fold at 2, 4, 6, and 8 w, and exhibited increased levels of pro-inflammatory intracellular IFNγ (40.5 ± 5.9 vs 28.4 ± 5.1%) and TNFα (34.6 ± 8.8 vs 21.7 ± 6.9%). Moreover, at 8 w post-MI, Tregs were increased in the spleen (24.1 ± 3.9 vs 18.3 ± 1.4%) and failing heart (0.95 ± 0.42 vs 0.33 ± 0.23%) as compared with sham mice. In contrast to splenic Tregs from sham mice, Tregs isolated from HF mice (8 w post-MI) failed to suppress effector T-cell proliferation, and were robustly antiangiogenic as indexed by mouse coronary endothelial cell tube formation assays. Transgenic mice expressing diphtheria toxin (DT) receptor (DTR) under control of the Foxp3 promoter underwent coronary ligation and DT-induced selective Treg ablation starting at 4 w post-MI (PBS control). Echocardiography before and after (8 w post-MI) PBS or DT injection revealed that in contrast to progressive LV dysfunction and remodeling after PBS, DT-mediated Treg ablation and subsequent reconstitution reversed pathological LV remodeling (decreased EDV and ESV, and increased EF). As compared with PBS injection, DT-induced Treg ablation also significantly (p < 0.05) reduced LV hypertrophy; enhanced circulating CD34+Flk1+ cells, cardiac CCR5 gene expression, and myocardial capillary density; reduced border zone fibrosis; and decreased pro-inflammatory (IL-17, IL-2 and IL-6) and pro-fibrotic (IL-4 and IL-10) serum cytokines. Similar results were obtained upon Treg depletion with anti-CD25 antibody in HF. We conclude that Tregs in chronic HF acquire pathological pro-inflammatory, profibrotic, and antiangiogenic properties, and lose their immunosuppressive capacity. Dysfunctional Tregs promote inflammation and adverse LV remodeling in HF; depletion of dysfunctional Tregs and subsequent restoration to a normal Treg phenotype may represent a novel approach to therapeutic immunomodulation in HF.Author Disclosures: S.S. Bansal: None. M. Goel: None. M. Ismahil: None. T. Hamid: None. H. Zhong: None. Y. Wu: None. S.D. Prabhu: None.