The aim of this study is to describe the efficacy and safety of CO2 fractional laser to treat striae distensae (SD), before (T0) and 1 month after the last laser session (T1), in patients following different protocols based on the number of laser sessions, ≤4 and > 4. Efficacy was estimated with global assessment improvement scale (GAIS) performed by both physicians and patients, reflectance confocal microscopy (RCM), dermatology life quality index (DLQI). Safety was evaluated through pain assessment and adverse events. Eighteen patients with SD were enrolled. Clinical improvement of SD was observed in all patients at T1, as compared to T0. Furthermore, a reduction of RCM features of SD was observed at T1, above all in patients receiving >4 treatments, as compared to T0. Interestingly, we describe herein a new RCM feature of SD, the "neat-wall", corresponding to a distortion of the normal dermo-epidermal junction (DEJ), with a well-demarcated margin. A significant improvement of DLQI (P-value = .007) was also registered after SD treatment. Adverse events included temporary erythema and edema. In conclusion, the current study confirms the efficacy and safety of fractional CO2 laser, proposing RCM features, such as parallel collagen fibers and the neat-wall, as potential markers of SD treatment response.