Background: Oral mucositis (OM) and dermatitis (RD) are serious side effects of radiotherapy (RT), often leading to its suspension, need for analgesics and enteral/parenteral nutrition. Laser-therapy is becoming a recommended option for mucosal lesions and has also been tested for skin affections. This prospective study investigates the effect of Laser-therapy (HPLT) on RT-induced OM and proposes an off-label use of HPLT to treat RD in breast-cancer patients and in RT-treated anal-carcinoma patients Methods: 53 cancer patients, during/after RT and/or chemotherapy, affected by OM, were treated with HPLT during 4 consecutive days (970nm, 2,5W, 35-6000Hz, 240s). Assessment of OM (WHO-SCALE: Grading objective Scale), pain (VAS: Visual Analogue Scale), functional ability, subjective parameters, site/severity of OM were recorded weekly for 21 days. 27 breast-cancer patients and 2 anal-carcinoma patients affected by RD were treated by HPLT every other day for 2 weeks (970nm/660nm, 2-1000Hz, 6W, 480s) and monitored weekly for one month for grade, discomfort, itching and bleeding. Results: Regarding OM, regressive improvement of WHO- SCALE from day 7 on, and of VAS from day 2 on (p < 0.000) was registered. All patients’ functional capacity improved on day 4 (p < 0.05). All subjective parameters improved on day 14 (p < 0.001) except voice, which improved on day 21 (p < 0.000). Ulcerations’ dimension and erythema’s severity decreased in all sites (p < 0.05). Regarding breast and anal RD, after 6 HPLT’s sessions, complete and progressive resolution of pain, bleeding and itching was registered (p < 0.002). All patients referred maximum satisfaction for receiving HPLT. Conclusions: Regardless of OM grade/site and of kind/site of tumor, HPLT was effective in healing OM. Moreover, HPLT resulted an innovative and highly effective therapy for RD, both in breast and anal lesions. To establish an effective treatment strategy for OM and RD is of paramount importance to improve life-quality of patients but can also be beneficial for the continuation of cancer therapy. Consequently, HPLT may become integral part of everyday-practice in the management of RT adverse effects.