Postoperative infections in the oral region are usually caused by anaerobic bacteria. While some authors claim that routine antibiotic prophylaxis is necessary after third molar surgery, others do not recommend this practice. The major subject of controversy is what constitutes postoperative infection. Previous studies that have examined the benefit of routine antibiotic prophylaxis have used several clinical symptoms (pain, swelling, and trismus) as indicators of infection; however, these clinical symptoms may be vague and unreliable, and cannot be evaluated scientifically. As a result, their use has only sparked more debate in this area of research. The present study assessed the value of routine antibiotic prophylaxis in impacted mandibular third molar surgery using acute-phase protein levels as potential indicators of early and late postoperative infection. Specifically, serum levels of C-reactive protein and alpha-1 antitrypsin were measured preoperatively and postoperatively in patients who received either prophylactic antibiotics or placebos. The results revealed no statistically significant difference between treated and control patients in terms of incidence of postoperative infection.