Despite several decades of advances in both minimally invasive techniques and antibiotic therapy, infection remains one of the more common complications of invasive procedures. Interventional radiology (IR) has traditionally been believed to be associated with lower infection rates than surgery. However, new interventional techniques, as well as more aggressive therapeutic interventions, have presented new challenges in relation to pharmacological management of postprocedural infection and pain. The risk of infection associated with IR procedures can never be completely eliminated, and the reasons for this are manifold, including more virulent organisms, ongoing and newly emerging antibiotic resistance, increased numbers of immunocompromised patients, and the adoption into everyday interventional practice of more aggressive interventional techniques such as chemoembolization, uterine fibroid embolization, and complex biliary intervention. Despite the widespread use of prophylactic antibiotics in IR, and the widely held belief that they are beneficial and are the standard of care, randomized controlled clinical trials have never validated the use of antibiotics in this setting. As such, an argument could be made not to use antibiotics at all for prophylaxis in IR. The purpose of this article is to discuss some of the issues relating to the use of prophylactic antibiotics, and what choice of antibiotics physicians make when they decide to use prophylaxis for IR procedures.