The purpose of this study was to determine whether the timing of the most recent cardiac implantable electronic device (CIED) procedure, either a permanent pacemaker or implantable cardioverter-defibrillator, influences the clinical presentation and outcome of lead-associated endocarditis (LAE). The CIED infection rate has increased at a time of increased device use. LAE is associated with significant morbidity and mortality. The clinical presentation and course of LAE were evaluated by the MEDIC (Multicenter Electrophysiologic Device Cohort) registry, an international registry enrolling patients with CIED infection. Consecutive LAE patients enrolled in the Multicenter Electrophysiologic Device Cohort registry between January 2009 and May 2011 were analyzed. The clinical features and outcomes of 2 groups were compared based on the time from the most recent CIED procedure (early, <6 months; late, >6 months). The Multicenter Electrophysiologic Device Cohort registry entered 145 patients with LAE (early = 43, late = 102). Early LAE patients presented with signs and symptoms of local pocket infection, whereas a remote source of bacteremia was present in 38% of patients with late LAE but only 8% of early LAE (p < 0.01). Staphylococcal species were the most frequent pathogens in both early and late LAE. Treatment consisted of removal of all hardware and intravenous administration of antibiotics. In-hospital mortality was low (early = 7%, late = 6%). The clinical presentation of LAE is influenced by the time from the most recent CIED procedure. Although clinical manifestations of pocket infection are present in the majority of patients with early LAE, late LAE should be considered in any CIED patient who presents with fever, bloodstream infection, or signs of sepsis, even if the device pocket appears uninfected. Prompt recognition and management may improve outcomes.