ObjectivesTo date, studies have only investigated the use of platelet-rich fibrin (PRF) after removal of third molars from the mandible or maxilla. Removal of the upper and lower third molars is typically combined into one session per side; therefore, this study aimed to investigate influence on PRF.Materials and methodsThis prospective, single-blinded, randomized controlled, clinical trial (split-mouth design) included 25 patients. After third molar removal, the test group’s sockets were treated with solid PRF clots, whereas the control group’s sockets were conventionally treated. The primary outcome was swelling, which was measured digitally and analogously. Secondary outcomes included trismus, pus, hematoma, and clinical attachment loss (CAL) of the second molars on days 1, 3, 7, and 14. Patient-centered outcome measures and the consumption of painkillers and antibiotics were recorded on days 0–7. The t-test for paired samples, Wilcoxon test, and Chi-Square test were used for statistical analyses.ResultsSwelling was significantly lower on day 14 in the test group (p < 0.05). No statistically significant differences were observed in pain, trismus, and CAL. In the test group, the number of painkillers taken and the number of days of intake were significantly lower (p < 0.05).ConclusionsPRF caused a reduction of painkiller consumption and in the days painkillers were needed. PRF significantly considerably reduced swelling after 14 days. Owing to the lack of differences in other parameters, the integration of PRF application into routine wisdom tooth removal is critical.Clinical relevancePRF affects the long-term outcomes of third molar removal by reducing swelling and reducing as well as shortening painkiller consumption.Trial registrationclinicaltrials.gov (NCT05089812).