Most studies have confirmed the beneficial effects of autologous bone marrow mononuclear cell (BMMC) transplantation on angina, myocardial perfusion, regional wall motion, and LV ejection fraction (LVEF). Cardiac resynchronization therapy (CRT) has also shown a beneficial effect in patients with heart failure (HF) and electrical/mechanical dyssynchrony. However, the relative contribution of BMMC and CRT in patients with ischemic HF and electromechanical dyssynchrony has never been investigated. The aim of this study was to evaluate the benefit of combining BMMC transplantation with CRT in patients with severe ischemic HF, left bundle branch block (LBBB), and mechanical dyssynchrony. Patients with ischemic HF, LVEF < 35%, LBBB, and mechanical dyssynchrony underwent intramyocardial transplantation of BMMC and CRTD system implantation. This randomized, single-blind, crossover study compared clinical and echocardiographic parameters during two follow-up periods: 6 months of active CRT (BMMC + CRTact) and 6 months of inactive CRT (BMMC + CRTinact). Physical performance was assessed by means of a 6-min walking test. Myocardial perfusion was evaluated by SPECT. Quality of Life (QoL) was assessed through the Minnesota Living with HF Questionnaire (MLwHFQ). Twenty-six patients (64 ± 7 years) were enrolled in the study. The distance covered by the patients during the 6-min walking test significantly increased in the BMMC + CRTinact phase (BMMC therapy only) in comparison with the baseline (269 ± 68 vs 206 ± 51; p = 0.007) and in the BMMC + CRTact phase (BMMC therapy + CRT) in comparison with the BMMC + CRTinact (378 ± 59 vs 269 ± 68; p < 0.001). The summed rest and stress score (SPECT) decreased significantly in the BMMC + CRTact and BMMC + CRTinact phases in comparison with the baseline (p ≤ 0.03). Both phases showed equivalent myocardial perfusion in the segments into which BMMC had been injected. QoL score was significantly lower in the BMMC + CRTinact phase than at the baseline (44.1 ± 14 vs 64.8 ± 19; p < 0.001), and in the BMMC + CRTact phase than in the BMMC + CRTinact phase (26.4 ± 12 vs 44.1 ± 14; p = 0.004). BMMC and CRT seem to act independently on myocardial perfusion and electromechanical dyssynchrony, respectively. Combining these two complementary therapies can significantly improve LV performance in patients with severe HF and electromechanical dyssynchrony.