Rationale: Allogeneic mesenchymal precursor cells (MPCs) have been effective in large animal models of ischemic and nonischemic heart failure (HF). Objective: To evaluate the feasibility and safety of 3 doses (25, 75, or 150 million cells) of immunoselected allogeneic MPCs in chronic HF patients in a phase 2 trial. Methods and Results: We sequentially allocated 60 patients to a dosing cohort (20 per dose group) and randomized them to transendocardial MPC injections (n=15) or mock procedures (n=5). The primary objective was safety, including antibody testing. Secondary efficacy end points included major adverse cardiac events (MACE; cardiac death, myocardial infarction, or revascularization), left ventricular imaging, and other clinical-event surrogates. Safety and MACE were evaluated for up to 3 years. MPC injections were feasible and safe. Adverse events were similar across groups. No clinically symptomatic immune responses were noted. MACE was seen in 15 patients: 10 of 45 (22 ) MPC-treated and 5 of 15 (33 ) control patients. We found no differences between MPC-treated and control patients in survival probability, MACE-free probability, and all-cause mortality. We conducted a post hoc analysis of HF-related MACE (HF hospitalization, successfully resuscitated cardiac death, or cardiac death) and events were significantly reduced in the 150 million MPC group (0/15) versus control (5/15; 33 ), 25 million MPC group (3/15; 20 ), and 75 million MPC group (6/15; 40 ); the 150 million MPC group differed significantly from all groups according to Kaplan-Meier statistics >3 years (P=0.025 for 150 million MPC group versus control). Conclusions: Transendocardial injections of allogeneic MPCs were feasible and safe in chronic HF patients. High-dose allogeneic MPCs may provide benefits in this population.