Background: Stomatitis is highly prevalent in patients with cancer treated with the mammalian target of rapamycin inhibitor everolimus; it usually has an early onset and may compromise treatment dose intensity and patients’ quality of life. Within the randomized controlled Stomatitis Prevention trial (STOP, ISRCTN14568888), we investigated the possibility of using a commercial natural multicomponent mouthwash (Orasol Plus^®) to prevent the development of stomatitis of any grade in patients with advanced renal cell carcinoma (RCC) treated with everolimus. Methods: Overall, 62 patients were randomized to receive either Orasol Plus in addition to oral hygiene or oral hygiene alone (31 patients per treatment arm). Results: In the whole study population, 28 episodes of stomatitis were observed (41.9%); in only 2 patients, stomatitis occurred more than once (2 episodes). As expected, the episodes of stomatitis occurred early in the course of treatment with everolimus. Treatment with Orasol Plus prevented the onset of everolimus-induced stomatitis: only 8 episodes of stomatitis were observed in the treated group with Orasol Plus in addition to oral hygiene vs 20 episodes in the group treated with oral hygiene only ( p = 0021). Also, a reduction in the average duration of mucositis in patients treated with Orasol Plus compared to patients treated with oral hygiene only was observed (8 days vs 11.2 days, p = 0.0416). Conclusion: This study showed that the use of a natural multicomponent mouthwash coupled with regular oral hygiene was able to reduce the severity and duration of everolimus-induced stomatitis in patients with RCC. Trial registration number: ISRCTN14568888