Background and aims <p>Cardiac implantable electronic devices (CIEDs) are essential for the management of cardiac arrhythmias. Device infection is one of the most dismal complications of CIED implantation. The aim of this study is to assess the role of postoperative oral antibiotics and the risk of CIED infection.</p> Methods <p>This retrospective analysis included 1,527 patients who underwent CIED implantation at a tertiary medical center. Patients were stratified to two groups based on the routine practice of their treating physicians. The primary outcome was a composite rate of skin infection, pocket infection, endocarditis or bacteremia within 6 months. Statistical analyses included univariable analysis, Kaplan–Meier analysis, estimation of a propensity score for antibiotic administration and multivariable generalized linear mixed model.</p> Results <p>Overall, 661 patients received postoperative antibiotics, and 886 did not. Median age was 73 years and 36% were females. Diabetes, COPD and past myocardial infarction were the most common comorbidities. Eighty percent had their first implantation. Infection rate was 1.3% in the no-antibiotic group and 2.1% in the antibiotic group, without a significant difference between the groups (p = 0.20). In multivariable analysis, younger age was borderline associated with an increased risk of infection, whereas administration of postoperative antibiotics was not.</p> Conclusions <p>The rate of CIED infections within 6 months after implantation was low without a significant difference between the groups. Given the global concern over antimicrobial resistance, a more selective approach of postoperative antibiotic therapy should be considered. Larger, prospective studies are needed to validate this hypothesis.</p> Graphical Abstract <p></p>