Background Transmyocardial laser revascularization (TMR) is currently clinically performed with either a CO2 or Ho:YAG laser for the treatment of severe angina. While both lasers provide symptomatic relief, there are significant differences in the laser–tissue interactions specific to each device that may impact their ability to enhance the perfusion of myocardium and thereby improve contractile function of the ischemic heart. Methods A porcine model of chronic myocardial ischemia was employed. After collecting baseline functional data with cine magnetic resonance imaging (MRI) and dobutamine stress echo (DSE), 14 animals underwent TMR with either a CO2 or Ho:YAG laser. Transmural channels were created with each laser in a distribution of 1/cm2 in the ischemic zone. Six weeks post-treatment repeat MRI as well as DSE were obtained after which the animals were sacrificed. Histology was preformed to characterize the laser–tissue interaction. Results CO2 TMR led to improvement in wall thickening in the ischemic area as seen with cine MRI (40.3% vs. baseline, P < 0.05) and DSE (20.2% increase vs. baseline, P < 0.05). Ho:YAG treated animals had no improvement in wall thickening by MRI (−11.6% vs. baseline, P = .67) and DSE (−16.7% vs. baseline, P = 0.08). Correlative semi-quantitative histology revealed a significantly higher fibrosis index in Ho:YAG treated myocardium versus CO2 (1.81 vs. 0.083, P < 0.05). Conclusions In a side-by-side comparison CO2 TMR resulted in improved function of ischemic myocardium as assessed by MRI and echocardiography. Ho:YAG TMR led to no improvement in regional function likely due to concomitant increase in fibrosis in the lasered area.