Indications for and prevalence of laser therapies with a fractionated laser beam have risen significantly. However, as of yet, little is known about the underlying molecular changes, especially with respect to dermal extracellular-matrix remodelling, wound healing and inflammation. This study aimed at the investigation of the connective tissue response of sun-damaged skin following fractionated laser treatment. Seven patients received a laser therapy on the lateral side of the neck of wrinkles grade III-IV (Glogau scale) using a fractionated thermo-ablative erbium yttrium aluminium garnet (Er:YAG) laser (2940 nm, BURANE XL; Quantel Derma, Erlangen, Germany). Skin biopsies were taken at baseline from untreated skin, 1 and 6 weeks after laser intervention to investigate hyaluronan (HA), collagen-I (Coll-I) and collagen-III (Coll-III) remodelling as well as alteration of matrix metalloproteinase 1 expression (MMP-1). To address this issue, HA synthesizing (HA synthetases, HAS) and degrading (hyaluronidases, HYAL) enzymes were measured at mRNA-level using a real-time PCR. Furthermore, immunohistochemical staining for HA was performed by using the HA binding protein (HAbP) and for Coll-I, Coll-III and MMP-1 by using monoclonal antibodies. The degree of inflammation was correlated descriptively. Our findings were that at the two examined read out points, HAS and HYAL showed a slight response alluding to HA synthesis under minimal signs of inflammatory reaction. Concordantly, although to a varying degree, an increase in the HA content of the skin after laser treatment could be detected by immunhistochemistry. During remodelling, Coll-I, Coll-III and MMP-1 showed a cyclic course with a peak after 1 week. Conclusively, our results indicate a light alteration of the HA metabolism towards synthesis and a transient collagen neogenesis caused by a single fractionated thermo-ablative laser skin intervention. Clinical improvement might be attributed to synergistic effects between collagen neogenesis and the water binding capacities of HA and its influence on skin contraction and remodelling.