© 2020, The Author(s).Objective: The aim of this study was to evaluate the effect of an iodine tampon on postoperative discomfort after surgical removal of a mandibular third molar. Material and methods: Patients were randomly assigned to two groups: one group received an alveolar iodine-containing tampon in the extraction socket (N = 44), and the other group used a disposable syringe (Monoject®) to rinse the wound (N = 43). Postoperative discomfort was assessed with the Oral Health Impact Profile-14 (OHIP-14) questionnaire, Pain Intensity Numerical Rating Scale (PI-NRS), and questions about self-care and discomfort. Results: This study included 87 patients (52 women and 35 men) with an average age of 26.47 years (SD, 6.36). The mean OHIP-14 sum scores were significantly lower in the iodine tampon group compared with the Monoject® syringe group. Mean PI-NRS scores significantly differed between the iodine tampon group (3.33; SE, 0.27) and Monoject® syringe group (4.46; SE, 0.27) (F (1, 85) = 8.16, p < 0.01), with no interaction effect between time and PI-NRS (F (6, 510) = 1.26, p = 0.28). Patients in the iodine tampon group reported less postoperative discomfort. Conclusions: Insertion of an iodine-containing tampon in the postoperative socket reduced the pain and impact on oral health-related quality of life during the first postoperative week and positively influenced postoperative sequelae.