Background: Secondary antimicrobial prophylaxis involves the use of ≥ 1 antimicrobial agent just prior to the time when a diagnostic/therapeutic procedure, which may induce infection, is to be performed. In the context of this article, antimicrobial agent(s) are administered to patients with ≥ 1 implanted prosthetic device in order to prevent metastatic seeding of the device(s) during bacteremia induced by a diagnostic/therapeutic procedure. Antimicrobial agents used in this context are only administered periprocedurally. Secondary antimicrobial prophylaxis of endocarditis in recipients of cardiac prosthetic materials (including valves, shunts, conduits, and patches) has been reasonably well established. However, secondary antimicrobial prophylaxis in recipients of other types of prosthetic devices has been the subject of much controversy, with a wide variety of recommendations being made. Objectives: The purpose of this article was to conduct a narrative review of the published literature on the topic of secondary antimicrobial prophylaxis in recipients of noncardiac prosthetic devices and make evidence-based recommendations for each type of device, where possible. Methods: Medline/PubMed and EMBASE databases were searched for English-language articles published from 1950 to the present (January 2012). Search terms included “prophylaxis,” “antibiotics,” “antimicrobials,” “prosthetic devices,” “prosthesis-related infections,” “bacteremia,” the names of the individual types of prosthetic devices, and the names of the individual procedures potentially inducing bacteremia. Articles dealing with any aspect relevant to this topic were eligible for review. The bibliographies of retrieved articles were also carefully scanned to identify any articles not previously identified. Results: Based on review of the available literature, secondary antimicrobial prophylaxis is justified in only a few specific circumstances. For recipients of prosthetic vascular grafts/stents, hemodialysis arteriovenous shunts, and ventriculoatrial/ventriculovenous shunts, prophylaxis is warranted during the initial 6 months, initial 6 weeks, and at all times after implantation/revision, respectively, when dental procedures capable of inducing high-level bacteremia are planned. Prosthetic joint recipients should receive prophylaxis in the following 3 circumstances: 1) patient is to undergo dental procedure(s) capable of inducing high-level bacteremia plus either the patient is still within 2 years of device implantation/revision or the patient has ≥ 1 risk factor for hematogenous prosthetic joint infection; 2) patient is to undergo genitourinary tract procedure(s) capable of inducing high-level bacteremia plus the patient has ≥ 1 risk factor for high-risk bacteriuria; and 3) patient is to undergo perforating dermatologic surgery on the oral mucosa or at skin sites at increased risk for surgical site infection plus patient has ≥ 1 risk factor for hematogenous prosthetic joint infection. The data are inadequate to justify secondary antimicrobial prophylaxis for recipients of other types of prosthetic devices. On the basis of 9 surveys of prescriber behavior, it is apparent that there exists, over a wide geographic area, a wide disconnect between clinical practice and the secondary antimicrobial prophylaxis guidelines issued by the professional organizations representing these prescribers. Antimicrobial agent overuse was especially problematic among orthopedic and colorectal surgeons, urologists, and family practitioners. Dentists and maxillofacial surgeons followed guidelines more closely. Conclusion: Device-, procedure-, and patient characteristic-dependent factors elicited over many years have narrowed down the secondary antimicrobial prophylaxis recommendations for noncardiac prosthetic devices to a small number. Despite this, physician prescribers frequently do not follow prophylaxis guidelines established by their own professional organizations. Risk-benefit and cost-effectiveness studies have found that no prophylaxis is actually superior to universal prophylaxis, likely due to known antimicrobial toxicities, such as anaphylactic/anaphylactoid reactions and Clostridium difficile–associated disease. Much work remains in establishing and extending the scientific basis for secondary antimicrobial prophylaxis and transforming this knowledge into appropriate action by the clinician.