OBJECTIVE: The primary endpoint of the present study was to assess the potential therapeutic effects of three different mouthwashes for alleviation and treatment of oral complications (OCs). The secondary endpoint was to assess patients' perceptions and daily functional activities after therapy of OCs in patients with colon cancer receiving 5-fluorouracil (5-FU)-based chemotherapy regimens. METHODS: A prospective, randomised controlled study carried out on 90 patients with colon cancer eligible for 5-FU-based chemotherapy regimens at the oncology centre, Istanbul, Turkey. Patients were randomly randomised into three groups (30 patients in each group) and received a single mouthwash. The first group (group A) received benzydamine at a dose of 15 mL; the second group (group B) received sodium bicarbonate at a dose of 1.2-2.4 g in 240 mL of water; and the third group (group C) received glutamine suspension 10 g. Patients were assessed for the occurrence of oral complications based on the WHO scale for oral mucosa evaluation and National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Oral pain was assessed using a visual analogue scale alongside assessment of patients' perceptions and daily functional activities based on the Rotterdam Symptom Checklist. RESULTS: A total of 119 oral complications were reported, including mouth dryness (n=56, 47.1%), oral mucositis (n=31, 26.1%) and oral pain (n=32, 26.8%). At the end of the study, patients of group A and group B significantly suffered from mouth dryness (p=0.0001), oral mucositis (p=0.029) and oral pain (p=0.039) compared with patients in group C. Although there was no significant change, group C patients showed a slight improvement in psychological discomfort, activity levels and quality of life at the end of the study. CONCLUSION: The present study showed that benzydamine and sodium bicarbonate mouthwashes were significantly less effective for the alleviation and treatment of oral complications compared with glutamine among patients with colon cancer receiving 5-FU-based chemotherapy regimens.