Treatment of keloids (K) and hypertrophic scars (HTS) is challenging. A few case reports reported good results in HTS treated by fractional CO2 laser. The aim of the present study was the assessment of the clinical response as well as histological changes in K and HTS treated by fractional CO2 laser and the role of matrix metalloproteinase 9 (MMP9) in the response. A randomized half of the scar was treated by fractional CO2 laser in 30 patients (18 K, 12 HTS) for a total of four sessions 6 weeks apart. Vancouver scar score (VSS) was done before and 1, 3, and 6 months after the last laser session by a blinded observer. Biopsies taken from normal skin, untreated scar, and treated scar tissue 1 and 3 months after the laser sessions were stained by HX & E for histological changes and Masson trichrome for collagen fiber arrangement. Immunohistochemical staining for MMP9 was done in before and 1 month after samples. Quantitative morphometric analysis was done for collagen and MMP9 by image analyzer. Nineteen patients completed the 6-month follow-up period (12 K, 7 HTS). VSS score was significantly lower in the treated compared to untreated areas after 3 and 6 months in both K and HTS but was mainly due to improved pliability of the scar. Histologically, dense inflammatory infiltrate and increased vascularity was apparent 1 month after laser sessions and disappeared at 3 months. Thinner better organized collagen bundle could be seen in 3 months after samples. MMP9 was significantly increased in after treatment samples but without significant correlation with VSS. Fractional CO2 resurfacing is safe but affects mainly pliability of K and HTS with collagen remodeling apparent 3 months after therapy. MMP9 may play a role in mechanism of action of CO2 laser in K and HTS.