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Introduction: Radiation therapy and chemotherapy are the standard treatment given for cancer, which leads to the variety of adverse effects of which Oral Mucositis (OM) is one of the common side-effects. It is responsible for patient discomfort and decreases their level of functioning. Both Chlorhexidine and Povidone Iodine have got antimicrobial and antifungal activity which decreases the severity of mucositis. Aim: To compare the effectiveness of Povidone Iodine and Chlorhexidine mouthwash on OM among cancer patients undergoing radiation therapy or chemotherapy. Materials and Methods: A prospective observational study was conducted in the tertiary care hospital of Mangaluru, Karnataka, India for the duration of one year and three months from December 2015-March 2017. Fifty cancer subjects aged between 25 to 65 years and who developed OM after radiation therapy or chemotherapy were selected by purposive sampling technique. Data were collected using the demographic profile, clinical proforma and World Health Organisation (WHO) OM grading scale (2004) from 19.09.2016 to 17.12.2016. Experimental group I received 10 mL of diluted Povidone Iodine mouthwash and group II received 10 mL of diluted chlorhexidine mouthwash. Level of OM in the group I and group II were assessed on the 1st, 3rd, 5th and 7th day using WHO OM grading scale (2004). The data were analysed by descriptive and inferential statistics (Wilcoxon signed-rank test, Mann-Whitney U test, Repeated measures ANOVA) using SPSS version 16.0. Results: Among the 50 cancer subjects, majority 30 (60%) were in the age group between 55-64 years and majority 35 (70%) were receiving radiation therapy. On day 7, in the group I (Povidone Iodine) majority 14 (56%) subjects had mild level of mucositis whereas in the group II (Chlorhexidine) majority 14 (56%) subjects had moderate mucositis. Comparison of the effect of Povidone Iodine and Chlorhexidine mouthwash using Friedman's ANOVA showed that there was a difference in the level of mucositis (p<0.05) at 5% level of significance among two groups. The study findings also revealed a difference in the level of mucositis between day 1 to day 3, 5 and 7 (Mann-Whitney U test) (p<0.05) in both the groups. Conclusion: Povidone Iodine mouth wash was more effective than Chlorhexidine mouthwashes in reducing OM, and the patients were more comfortable after the use of the mouthwash. [ABSTRACT FROM AUTHOR]