To increase the angiogenic response and clinical efficacy of TMR, the potential synergy and safety of combining TMR with concentrated autologous bone marrow derived stem cells was evaluated. Fourteen patients with diffuse coronary artery disease and medically refractory class III/IV angina who were not candidates for conventional therapies were treated using TMR in combination with intramyocardial injection of concentrated stem cells. At the time of surgery, autologous bone marrow (120 cc) was aspirated from the iliac crest and processed over 15 min into 20 cc of concentrated mononuclear cells using a centrifugal system (HARVEST, Boston, MA). A single device performed holmium: YAG:TMR (CardioGenesis, Irvine, CA) with injection of 1 cc of concentrated stem cells through three multi-holed needles into the border zone around each laser channel. There were no perioperative adverse events including no arrhythmias. Mean number of injected cells per milliliter were: total mononuclear cells (81.3 x 10(6)), CD34(+) cells (0.6 x 10(6)), and CD133(+) cells (0.37 x 10(6)). At 7 months mean follow-up average angina class was significantly improved (3.5+/-0.5 vs 1.4+/-0.5; p=0.004). There was no death during the follow-up. Efficient delivery of stem cells combined with TMR in a single device seems to be safe and effective for treating unmanageable angina.