Lichen sclerosus (LS) is an inflammatory and chronic disease that causes itching, pain, dysuria, urinary retention, dyspareunia and sexual dysfunction, in both men and women. The first line pharmacological treatment is based on the use of topical steroids, which have proved their efficacy in 60-70% of cases but with a high rate of relapses in time (50-80% of the patients of both sexes). The purpose of our non-randomised prospective pilot study was to evaluate the efficacy and tolerability of a new loco regional therapy with polydeoxyribonucleotides (PDRN) in the treatment of male genital LS. PDRN is an healing and anti-dystrophic drug with anti-inflammatory effects, through the reduction of cytokine. Twenty one male patients suffering from genital LS were recruited. All the patients were submitted to treatment using loco-regional intradermal injections with PDRN. Dermatology Life Quality Index (DLQI), International Index of Erectile Function (IIEF-5) and PGI-I questionnaires were administered at baseline and at the end of treatment in order to evaluate the results of this treatment. The statistical evaluation of the data obtained with the DLQI questionnaire showed a marked improvement of the overall conditions in terms of quality of life, with an average change of scores from 15 to 4 (p < 0.0001). PGI-I questionnaire showed that 80% of the patients treated considered their post-treatment conditions as ‘improved'. There was no significant change in terms of sexual function according to the IIEF questionnaire (p = 0.189). The results obtained show the excellent tolerability and the therapeutic efficacy of PDRN, with clear improvement of the local symptoms and of the quality of life.