Previous studies suggested that transplantation of autologous bone marrow-derived mononuclear cells (BMNCs) improves heart function in chronic chagasic cardiomyopathy. We report the results of the first randomized trial of BMNC therapy in chronic chagasic cardiomyopathy. Methods and Results—Patients 18 to 75 years of age with chronic chagasic cardiomyopathy, New York Heart Association class II to IV heart failure, left ventricular ejection fraction (LVEF) 35%, and optimized therapy were randomized to intracoronary injection of autologous BMNCs or placebo. The primary end point was the difference in LVEF from baseline to 6 and 12 months after treatment between groups. Analysis was by intention to treat and powered to detect an absolute between-group difference of 5%. Between July 2005 and October 2009, 234 patients were enrolled. Two patients abandoned the study and 49 were excluded because of protocol violation. The remaining 183 patients, 93 in the placebo group and 90 in the BMNC group, had a trimmed mean age of 52.4 years (range, 50.8–54.0 years) and LVEF of 26.1% (range, 25.1%–27.1%) at baseline. Median number of injected BMNCs was 2.20 108 (range, 1.40–3.50 108). Change in LVEF did not differ significantly between treatment groups: trimmed mean change in LVEF at 6 months, 3.0 (1.3– 4.8) for BMNCs and 2.5 (0.6–4.5) for placebo (P 0.519); change in LVEF at 12 months, 3.5 (1.5–5.5) for BMNCs and 3.7 (1.5– 6.0) for placebo (P 0.850). Left ventricular systolic and diastolic volumes, New York Heart Association functional class, Minnesota quality-of-life questionnaire, brain natriuretic peptide concentrations, and 6-minute walking test did also not differ between groups. Conclusion—Intracoronary injection of autologous BMNCs does not improve left ventricular function or quality of life in patients with chronic chagasic cardiomyopathy