Although the application of cardiac implantable electronic devices (CIED) has greatly increased over the past few decades, CIED endocarditis is becoming a challenging scenario in clinical practice. Recently, Staphylococcus lugdunensis has emerged as a pathogen in CIED endocarditis. However, a detailed phenotypic characterization has not been addressed. We conducted a systematic literature review covering the period between 1989 and 2011 using the PubMed, Medline, Cochrane, and Embase databases. All cases included had a CIED in use and met the modified Duke criteria for infective endocarditis, and all had isolates of S. lugdunensis. The clinical features, predisposing conditions, echocardiographic findings, and therapeutic strategies/outcomes were evaluated. Polymorphonuclear neutrophil functions were examined to test whether the defect of innate immunity may play a permissive role in host susceptibility to tissue destruction in S. lugdunensis endocarditis. Eleven patients with CIED endocarditis caused by S. lugdunensis were identified. Their mean age was 61.7±11.2 years, and there was a male preponderance (72.7%). Six patients (54.5%) had undergone re-manipulation of the pacing system within a few months to years before the occurrence of clinical symptoms. The median time of symptoms before the diagnosis of CIED endocarditis was 60 days. On echocardiography, vegetations in the CIED were detected in nine cases (81.8%). Nine patients (81.8%) underwent surgical removal of the entire device, and one patient received medical treatment alone. The overall mortality rate was 18.2%. One patient had a septic perforation of the ventricular septum, with a high serum level of N-terminal prohormone of brain natriuretic peptide (NT-pro-BNP) in the absence of pump failure. The assessment of polymorphonuclear neutrophil (PMN) functions revealed normal PMN responses to the various stimuli and normal oxidative burst responses. Identification and differentiation of staphylococcal species in a timely manner would allow us to intervene more aggressively at an earlier stage to prevent unfavorable outcomes. Clinicians should never consider the isolation of S. lugdunensis as contamination. In selected individuals, therapeutic abstention may be preferable to exposing patients to a high risk of S. lugdunensis CIED endocarditis due to re-manipulation of the pacing system. The prognostic value of NT-pro-BNP warrants further investigations.