Structural heart disease, intravascular catheters, and invasive procedures are predisposing factors for infective endocarditis (IE). Data on IE in children with structurally normal hearts and no predisposing factors are limited. We aim to characterize IE (definite or possible by Duke criteria) in such a subgroup of pediatric patients (age <18 years) who were treated at our medical center. Of 51 events of IE in 50 children, 9 (18 %) had no predisposing factors. These infections were all community-acquired and presented with fever, a newly detected heart murmur, diagnostic echocardiographic findings, and left-sided infection. Clinical course was characterized by acute onset (n = 8 of 9) with a 100 % complication rate (heart failure or embolic phenomena). Emergency cardiac surgery was performed in 7 children (Ross surgery [n = 4], mitral valve replacement [MVR; n = 2], and valve repair [n = 1]). Causative organisms were S. aureus (n = 3), S. pneumoniae (n = 2), H. parainfluenzae (n = 1), and K. kingae (n = 1). In contrast, IE in children with predisposing factors (42 of 51 [82 %]) was frequently health care-associated (30 of 42), right-sided (20 of 42, p = 0.041), and with lower rates of diagnostic echocardiographic findings (28 of 42, p = 0.041), complications (16 of 42, p < 0.001), and surgical intervention (9 of 42, p = 0.002). Causative organisms were mainly viridans streptococci (n = 9), Candida species (n = 8), coagulase-negative staphylococci (n = 6), enteric Gram-negative bacilli (n = 6), S. aureus (n = 5), and K. kingae (n = 3). Mortality was 11 % in both groups. We conclude that pediatric IE in children with and without predisposing factors differs significantly. Due to the acute and complicated course of the latter, high awareness among pediatricians and prompt diagnosis are crucial.