BACKGROUND: Oral mucositis (OM) is one of the most common complications of mucotoxic cancer therapy. Mucositis induces clinically significant pain, increases the risk of infections and affects the patients' quality of life. OBJECTIVE: This study investigated the effects of an herbal preparation from Plantago ovata hydrocolloid in the prevention and treatment of OM, in breast cancer patients undergoing chemotherapy with a regimen including adriamycin. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: This research was a double-blind, randomized, controlled crossover trial. The herbal compound consisted of a mixture of 500 mg of P. ovate husk in 30 mL water plus three drops of vinegar per dose, which was used as a mouthwash. Phytochemical and physicochemical tests of the compound were also performed. Twenty-eight patients who developed mucositis during the chemotherapy screening cycle were randomized to the herbal compound (n = 14) and placebo (n = 14) groups. They received herbal compound or placebo three times per day during their next chemotherapy cycle (cycle 1 of treatment). Patients were crossed over during cycle 2 of treatment and received the alternative therapy. An oral care protocol was prescribed to all patients in cycles 1 and 2 of the treatment. MAIN OUTCOME MEASURES: The patients were visited at baseline, the end of the first and second weeks of the screening cycle, and the end of the first and second weeks of each of two treatment cycles. The degree of mucositis was used as the main treatment outcome. Other indexes, such as the severity of pain, xerostomia grade and the quality of life were also measured. RESULTS: Compared with the placebo, the herbal compound significantly reduced the degree of mucositis, the severity of pain and the xerostomia grade; it also improved the patients' quality of life (P < 0.05). Comparison between the screening cycle and placebo treatment group showed that the oral care protocol had a significant effect in the reduction of OM (P < 0.05). CONCLUSION: The oral care protocol and the herbal compound based on P. ovata are effective ways for preventing and treating OM in patients undergoing mucotoxic cancer therapy. TRIAL REGISTRATION Iranian registry of clinical trials IRCT20180923041093N1.