Objective. This double-blind randomized clinical trial evaluates the efficacy and route of administration of omega-3 fatty acids for the prevention and treatment of oral mucositis in patients undergoing chemotherapy in Iranian hospitals. Materials and Methods. Sixty patients developing World Health Organization (WHO) grade 1 oral mucositis were randomized to the omega-3 fatty acid (n=30) or placebo (n=30) group. Mucositis was assessed according to the WHO, Western Consortium for Cancer Nursing Research, and Oral Mucositis Weekly Questionnaire criteria at baseline and first, second, and third weeks of chemotherapy until mucositis resolved. Results. Differences in the severity of mucositis between the omega-3 and placebo groups in the first, second, and third weeks of treatment based on the WHO criteria were noted. This study showed that patients in the omega-3 group experienced less pain during the first, second, and third weeks of treatment. Conclusions. Omega-3 fatty acids are a safe, effective method for preventing and treating oral mucositis in patients receiving mucotoxic cancer chemotherapy.