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The aim of this study was to evaluate the CO2 waveguide laser (WG CO2 laser) with flexible fiber (Lumenis Ltd., Yokneam, Israel) in the treatment of oral and oropharyngeal cancers, specifically focusing on postoperative outcomes, pain, and quality of life (QoL). Eighty-one patients, 43 women and 38 men, with oral or oropharyngeal cancer who consecutively underwent transoral resection by WG CO2 laser from August 2015 to April 2020 were retrospectively enrolled. Resections were performed in super pulsed mode with a power setting ranging between 3 and 10 W. Data about frozen sections, reconstruction, complication rate, length of hospital stay, tracheostomy rate and time to decannulation, nasogastric feeding tube rate and time to oral feeding, pain, and QoL were reviewed. Continuous variables were presented as mean and standard deviation. Concordance between intraoperative frozen section examination and definitive histology was calculated using Cohen's K test of agreement. The mean length of hospital stay was 13 days. The feeding tube rate was 81%; the tracheostomy rate was 35%; the feeding tube was left in place for 8 days on average, and the time to decannulation was 9 days. The only complication was a postoperative bleeding in 4 patients. The median postoperative pain score measured by the Numeric Pain Rating Scale on postoperative days 1, 3, and 5 was 0 and there was a constant decrease in painkiller use over the days. The overall mean composite QoL score was 77 ± 14, with excellent results in saliva, taste, pain, and speech domains. Frozen section evaluation had a specificity of 99% and a negative predictive value of 98%. WG CO2 laser is a good and safe tool for transoral tailored resection of oral and oropharyngeal cancers. It ensures a good overall QoL and guarantees fast recovery and a very low postoperative pain. [ABSTRACT FROM AUTHOR]