In the 1960s, carbon dioxide (CO2) laser therapy started to be applied to eliminate wrinkles, actinic scars, and acne because of its capacity of induce intracellular water vaporization. However, recent studies have shown the efficacy of the erbium laser in removing delicate and moderate scars. Furthermore, the postoperative lesions induced by the erbium laser seem to resolve faster and with less erythematous pattern compared with lesions induced by the CO2 laser. The purpose of this study was to determine the immediate pathologic alterations caused by single applications of CO2 and erbium lasers and their association in human skin shreds. Ten white female patients aged 30 to 63 years underwent rhytidectomy, and their respective shreds, which were prepared for excision, were tattooed with the CO2 laser, the erbium laser, or a combination of both in random order and number of applications, before final removal. This project was approved by the local ethical committee. After surgical removal, these tattooed shreds were fixed in 10% buffered formalin and submitted to histopathologic analysis. Morphometric studies demonstrated the normal skin thickness and thickness of the laser-treated area, and their subtraction resulted in the ablation damage values. Residual thermal damage corresponded to the thickness of the affected skin from the most superficial layer of tissue in the laser-treated area down to the deepest dermal area with basophilic degeneration of collagen fibers. Our results showed that two CO2 applications resulted in greater ablation and residual thermal damage when compared with only one CO2 application. The same was true in comparisons of one and two applications of the erbium laser. Both results were statistically significant (p < 0.05). When one isolated erbium and one isolated CO2 application were compared, ablation damage was greater in the former group, although with no statistical significance. One CO2 plus one erbium application compared with one isolated CO2 application showed similar ablation damage but greater residual thermal damage in the latter group (p < 0.05). These observations might contribute to our understanding of the lesions caused in the human skin by erbium and CO2 lasers and eventually help determine the ideal laser combination for the appropriate surgical treatment.