Mononuclear stem cells have been studied for their potential in myocardial ischemia. In our previous published article, ReACT(®) phase I/II clinical trial, our results suggest that a certain cell population, promonocytes, directly correlated with the perceived angiogenesis in refractory angina patients. This study is ReACT's clinical update, assessing long-term sustained efficacy. The ReACT phase IIA/B noncontrolled, open-label, clinical trial enrolled 14 patients with refractory angina and viable ischemic myocardium, without ventricular dysfunction, who were not suitable for myocardial revascularization. The procedure consisted of direct myocardial injection of a specific mononuclear cell formulation, with a certain percentage of promonocytes, in a single series of multiple injections (24-90; 0.2 ml each) into specific areas of the left ventricle. Primary endpoints were Canadian Cardiovascular Society Angina Classification (CCSAC) improvement at the 12-month follow-up and ischemic area reduction (scintigraphic analysis) at the 12-month follow-up, in correlation with ReACT's formulation. A recovery index (for patients with more than 1 year follow-up) was created to evaluate CCSAC over time, until April 2011. Almost all patients presented progressive improvement in CCSAC beginning 3 months (p=0.002) postprocedure, which was sustained at the 12-month follow-up (p=0.002), as well as objective myocardium ischemic area reduction at 6 months (decrease of 15%, p<0.024) and 12 months (decrease of 100%, p<0.004) The recovery index (n=10) showed that the patients were graded less than CCSAC 4 for 73.9 ± 24.2% over a median follow-up time of 46.8 months. After characterization, ReACT's promonocyte concentration suggested a positive correlation with CCSAC improvement (r=-0.575, p=0.082). Quality of life (SF-36 questionnaire) improved significantly in almost all domains. Cost-effectiveness analysis showed decrease in angina-related direct costs. Refractory angina patients presented a sustained long-term improvement in CCSAC and myocardium ischemic areas after the procedure. The long-term follow-up and strong improvement in quality of life reinforce effectiveness. Promonocytes may play a key role in myocardial neoangiogenesis. ReACT dramatically decreased direct costs.