Radiation-induced fibrosis (RIF) is one of the severe long-term side effects of radiation therapy (RT) with a crucial impact on the development of postoperative wound healing disorders (WHD). The grades of fibrosis vary between mild to severe depending on individual radiosensitivity. In this study, we have investigated the molecular pathways that influence RIF and have correlated data from immunohistochemistry (IHC) for von –Willebrand Factor (vWF) and from Real-Time Polymerase Chain Reaction (RT-PCR) concerning markers such as Transforming Growth Factor (TGF)-β 1, and vWF, with clinical data concerning the occurrence of WHD during follow-up. Expression profiles of the genes encoding TGF-β 1, vWF, and α-procollagen (PC) were analyzed, by RT-PCR, in specimens from patients with (n = 20; 25.6 %) and without (n = 58; 74.4 %) a history of previous RT to the head and neck. Moreover, IHC against vWF was performed. Clinical data on the occurrence of cervical WHDs were analyzed and correlated. A statistically significant increase in the expression profiles of α-PC and TGF-β 1 was observed in previously irradiated skin samples (occurrence of RT >91 days preoperatively). vWF showed a statistically significant increase in non-irradiated tissue. Moreover, analysis of expression profiles in patients with and without WHDs during follow-up was performed. IHC showed a reduced amount of vessels and structural changes in epidermal tissue post-RT. The expression of markers of fibrosis and angiogenesis was analyzed in order to gain insight into molecular pathways that account for structural changes in irradiated skin and that eventually lead to WHDs. The results are congruent with reports from the literature and are a possible starting point for further research, as anti-TGF-β 1 treatment, for example, could represent new therapeutic opportunities in the management of previously irradiated patients.