Purpose: The purpose of this prospective study was to compare the efficacy of prophylactic antibiotic regimens commonly used in dental implant surgery. Preoperative single-dose and long-term prophylactic antibiotic regimens were compared. Materials and Methods: This was a 2-center prospective study in which 215 patients underwent ambulatory endosseous implant placement. In the first group, 445 dental implants were placed in 125 patients after the administration of a single preoperative dose of prophylactic antibiotic with no postoperative antibiotics. In the second group, 302 dental implants were placed in 90 patients who received a preoperative dose of antibiotics and were instructed to take antibiotics postoperatively for 7 days. In both groups, 0.12% chlorhexidine pre- and postoperative mouth rinses were used. Patients returned for postoperative evaluation at 1 week, 2 weeks, and just prior to surgical uncovering. The surgical sites were assessed for pain, swelling, erythema, and purulence. Results: In the first group, 3 patients developed wound dehiscence at 5 implant sites and 1 developed a minor inflammatory response. None of the patients in this group received further antibiotics. In the second group, 3 patients developed wound dehiscence, 2 developed an inflammatory response, and 1 was diagnosed with infection, for which another course of antibiotics was required. There was no statistical difference between the 2 groups according to the Fisher 2 × 4 exact test (P = .56). Discussion: Indiscriminate use of antibiotics is unacceptable in clinical practice today. Surgeons must adhere to basic principles to gain the most benefit from the use of prophylactic antibiotics. Conclusion: Long-term prophylactic antibiotic use in implant surgery was of no advantage or benefit over a single-dose preoperative antibiotic regimen in this patient population.