Staphylococcus lugdunensis is a major cause of aggressive endocarditis, but it is also responsible for a broad spectrum of infections. The differences in clinical and molecular characteristics between community-associated (CA) and health care-associated (HA) S. lugdunensis infections have remained unclear. We performed a retrospective study of S. lugdunensis infections between 2003 and 2014 to compare the clinical and molecular characteristics of CA and HA isolates. We collected 129 S. lugdunensis isolates in total: 81 (62.8%) HA isolates and 48 (37.2%) CA isolates. HA infections were more frequent than CA infections in children (16.0% versus 4.2%, respectively; P ؍ 0.041) and the elderly (38.3% versus 14.6%, respectively; P ؍ 0.004). The CA isolates were more likely to cause skin and soft tissue infections (85.4% versus 19.8%, respectively; P < 0.001). HA isolates were more frequently responsible for bacteremia of unknown origin (34.6% versus 4.2%, respectively; P < 0.001) and for catheter-related bacteremia (12.3% versus 0%, respectively; P ؍ 0.011) than CA isolates. Fourteen-day mortality was higher for HA infections than for CA infections (11.1% versus 0%, respectively). A higher proportion of the HA isolates than of the CA isolates were resistant to penicillin (76.5% versus 52.1%, respectively; P ؍ 0.004) and oxacillin (32.1% versus 2.1%, respectively; P < 0.001). Two major clonal complexes (CC1 and CC3) were identified. Sequence type 41 (ST41) was the most common sequence type identified (29.5%). The proportion of ST38 isolates was higher for HA than for CA infections (33.3% versus 12.5%, respectively; P ؍ 0.009). These isolates were of staphylococcal cassette chromosome mec element (SCCmec)type IV, V, or Vt. HA and CA S. lugdunensis infections differ in terms of their clinical features, outcome, antibiotic susceptibilities, and molecular characteristics. S taphylococcus lugdunensis was first described by Freney et al. in 1988 (1). It has emerged as an important human pathogen in recent years, due to its ability to cause endocarditis and a broad spectrum of other infections, including skin and soft tissue infections, bloodstream infections, bone and joint infections, central nervous system infections, and intra-abdominal infections (2).S. lugdunensis has a lower incidence than Staphylococcus aureus and Staphylococcus epidermidis (3-5). Many studies have focused on cases of bacteremia and endocarditis caused by S. lugdunensis and have shown that this bacterium can, like S. aureus, cause invasive infections but with higher rates of complications and mortality (4, 6-10). Endocarditis due to this bacterium has been reported to be mostly community associated (CA) (4, 7). Two retrospective studies showed that most CA S. lugdunensis infections were skin and soft tissue infections, with a total absence of oxacillin resistance (11, 12). We recently reported 48 cases of invasive S. lugdunensis infection. Most of these cases (43 of 48 [89.6%]) were health care-associated (HA) infections, and the frequency ...