Background The growing resistance of bacteria to antimicrobial medicines is a global issue and a direct threat to human health. Despite this, antibiotic prophylaxis is often still routinely used in dental implant surgery to prevent bacterial infection and early implant failure, despite unclear benefits. There is a lack of sufficient evidence to formulate clear clinical guidelines and therefore there is a need for well-designed, large-scale randomized controlled trials to determine the effect of antibiotic prophylaxis. Purpose To compare the effect of a presurgical antibiotic regimen with an identical placebo regimen in healthy or relatively healthy patients receiving dental implants. Materials and Methods The 474 patients participating in the study were recruited from seven clinics in southern Sweden. We randomized the patients into a test and a placebo group; the study was conducted double-blinded. Preoperatively, the test group received 2 g of amoxicillin and the control group, identical placebo tablets. The primary outcome was implant failure; secondary outcomes were postoperative infections and adverse events. Patients were evaluated at two follow-ups: at 7-14 days and at 3-6 months. Results Postoperative evaluations of the antibiotic (n = 238) and the placebo (n = 235) groups noted implant failures (antibiotic group: six patients, 2.5% and placebo group: seven patients, 3.0%) and postoperative infections (antibiotic group: two patients, 0.8% and placebo group: five patients, 2.1%). No patient reported any adverse events. Between-group differences in implant failures and postoperative infections were nonsignificant. Conclusion Antibiotic prophylaxis in conjunction with implant placement is likely of small benefit and should thus be avoided in most cases, especially given the unabated growth in antibiotic-resistant bacteria. Clinical trial registration number: NCT03412305.