Although the demographic characteristics of patients who develop infective endocarditis (IE) have changed over the last few decades, Enterobacteriaceae remain rarely responsible. We report the clinical and epidemiological characteristics of 9 patients with native-valve Enterobacteriaceae IE from 6 French medical intensive care units over a 10-y period and have identified 29 additional cases in the literature. Nearly a third of the 38 patients were immunocompromised and/or had previously known valvular heart disease. Salmonella spp. and Yersinia spp. were the most frequently isolated microorganisms reported in the literature. The overall mortality rate was 24% (9/38) and was lower for operated patients (10% (1/10)) compared to those who did not undergo valve surgery (31% (8/26)). Our results confirmed the rarity of native-valve endocarditis caused by Enterobacteriaceae, pathogens frequently responsible for nosocomial and community-acquired bacteraemias. This paradox may be explained by susceptibility to the bactericidal action of serum and the inability of these bacteria to colonize the endocardium.