Background. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants exhibit different phenotypes and clinical manifestations in comparison to non-mutated viruses. Spike gene target failure (SGTF) is a characteristic feature of the gene in a novel variant that is recognized as highly transmissible. Several studies have demonstrated the virucidal effects of mouthwashes on SARS-CoV-2. Moreover, mouthwashes have proven beneficial for patients undergoing oral and maxillofacial surgery. Objectives. The present study aimed to analyze the effects of 2 different types of mouthwash (0.2% chlorhexidine gluconate and 1% povidone-iodine) on the cycle threshold (CT) values in coronavirus disease 2019 (COVID-19) patients with and without SGTF. Material and methods. This single-blind, non-randomized controlled clinical trial comprised 45 patients who were divided into 3 groups based on the intervention method: 0.2% chlorhexidine gluconate mouthwash; 1% povidone-iodine mouthwash; and mineral water (control group). The patients were instructed to gargle with the assigned solution 3 times a day for 5 days. Reverse transcription polymerase chain reaction (RT-PCR) tests were conducted at the time of initial diagnosis and on days 3 and 5. A normality test (Shapiro–Wilk test) was performed. Consequently, the non-parametric Friedman test was used. Results. The analysis revealed that the subjects who utilized mouthwashes exhibited higher CT values in comparison to the control group. Furthermore, 73% of patients who used 0.2% chlorhexidine gluconate presented with increased CT values, as indicated by a negative RT-PCR test on the 3rd day. Conclusions. Gargling with 0.2% chlorhexidine gluconate or 1% povidone-iodine for 30 s for at least 3 days has been demonstrated to increase CT values in both SGTF and non-SGTF COVID-19 patients. Hence, using the mouthwash may be considered for preoperative use in patients undergoing oral and maxillofacial surgery. © by Author(s).