<b><i>Background/Aims:</i></b> There is no treatment, without side effects, efficiently preventing or curing skin burns, caused by radiotherapy. A new experimental topical treatment protocol was assessed in mice receiving orthovoltage X-rays at an equivalent dose to that applied to human breast cancer patients in conventional radiotherapy. <b><i>Methods:</i></b> SKH-HR2 female hairless mice were irradiated on their dorsum with a total dose of 4,300 cGy during a 1-month period (20 fractions). The treatment group received a combination of 3 topical products, an oil-in-water cream, a gel containing <i>Pinus halepensis</i> bark aqueous extract, and an ointment containing olive oil extract<i></i> of the marine isopod <i>Ceratothoa oestroides</i>. The positive control group was treated with a conventionally used commercial gel, whereas the negative control group did not receive any topical treatment. Skin alterations were evaluated by macroscopic examinations, measurements of transepidermal water loss (TEWL), melanin content, erythema intensity, hydration, and histopathology assessment. <b><i>Results:</i></b> Sixty days after radiation, TEWL and hydration values were abnormal and elements of acute, chronic, and granulomatous inflammation were present in all cases. The severest damage was detected in the deeper dermis. Treatment showed a comparatively beneficial effect on chronic and granulomatous inflammation while positive control was beneficial on acute inflammation. <b><i>Conclusion:</i></b> Skin anti-inflammatory treatment was the most effective but must be applied for several months. Further preclinical studies should be conducted, assimilating a human cancer radiation therapeutic schema with the aim of optimizing skin inflammation treatment.