Introduction: Different guidelines and different regimens for prevention of infective endocarditis following operative procedures have been recommended. The purpose of this review was to explore the effectiveness of using antibiotics as prophylaxis in the prevention of IE in dental practice. Methods: The systematic search was conducted in the Medline, Science direct, CINAHL databases using search terms of (Infective endocarditis) AND (Epidemiology OR Bacteriology OR Prevention) AND (Dent*). The relevant information was extracted from eligible studies. The irrelevant, duplicated studies were excluded. Results: The antibiotic prophylaxis efficacy to prevent IE has never been assessed in a randomized controlled trial (RCT), and the profession has hedged far from such investigation on the grounds of numbers of patients required and ethical concerns. Perhaps the time has come for address this issue, a staged approach could be useful that is focusing a specific cardiovascular condition such as mitral valve prolapse in relation to operative dental procedures with low risk include endodontics and supragingival scaling. Conclusions: A multi-center approach will be required, but at least an RCT would confirm whether antibiotic prophylaxis is required and also assess the (risk/benefits) of the antimicrobial administered.