Both erbium (Er:YAG) and carbon dioxide (CO(2)) devices are commonly-used, efficient laser systems for aggressive skin resurfacing procedures. The devices each have different adjustable parameters (density, spot size, number of pulses, pattern, etc) and utilize variable energy capabilities to tailor individual treatments depending on the skin pathology and goals of treatment. Overall, the consensus has been that multiple-pass erbium treatments needed for efficacious wrinkle reduction had similar downtime and comorbidity to the traditional CO(2) treatments. Unfortunately, there were limited data comparing the histological differences and changes throughout the wound-healing process over time between the two treatment methods. The authors compare the difference in injury following treatment with five novel fractional ablative laser systems in vivo. Differences in damage pattern, treatment depth, and degree of surrounding cellular injury following treatment with each device at common clinical settings are evaluated in a side-by-side histopathologic comparison. Prior to planned excisional surgery, the panni of 20 abdominoplasty patients were treated with five novel ablative fractional carbon dioxide or Er:YAG laser systems at various clinical parameters, in accordance with the manufacturers' treatment guidelines. After tissue removal two to four hours later, the skin was biopsied and processed for histopathologic evaluation. Specimens were stained with hematoxylin and eosin, along with a terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) assay, to highlight the degree of irreversible cellular injury. The acute damage profile differed between the fractional Er:YAG and CO(2) devices with respect to depth of penetration and extension of coagulation surrounding the microcolumns. The damage pattern was dependent on the parameters set with each device (eg, fluence, pulses, density, pulse width). The TUNEL-stained sections demonstrated more collateral cellular injury surrounding the ablated columns with the CO(2) devices than with the Er:YAG systems. Following treatment with the fractional Er:YAG and CO(2) devices, deep tissue injury with various coagulative and ablative properties was observed, and it was confirmed that carbon dioxide and erbium devices result in different patterns of injury. As such, each may be better suited for different clinical situations. It is important for practitioners to understand the limitations of a specific device, as well as the tissue injury following a given treatment pattern or protocol, to appropriately tailor their treatment algorithm for a given patient. This extensive histopathologic evaluation of the acute characterization of injury across devices is helpful in clarifying the differences/similarities in laser-tissue interaction following treatment in an in vivo human model.