Background: Unlike Escherichia coli bacteremia, which is common, E. coli endocarditis is uncommon, particularly in patients with native valve, leading to its delayed diagnosis.Case Presentation: We present a case of infective endocarditis caused by E. coli in a 78-year-old Japanese man with type 2 diabetes, involving persistent bacteremia and vegetation on the mitral valve (measuring 18 × 4.2 mm in diameter). He presented with recurrent fever after antimicrobial treatment for pyelonephritis. He received antibiotic therapy for 6 weeks and required surgical removal of a calcified amorphous tumor and vegetation with mitral valvuloplasty 7 days after admission. Despite an episode of multiple cerebral infarctions, he recovered fully from the infection.Conclusions: Follow-up blood cultures should be performed for Gram-negative bacilli bacteremia among patients with unknown focus and an atypical clinical course after treatment. Early diagnosis and aggressive surgical intervention are paramount to achieving good clinical outcomes. [ABSTRACT FROM AUTHOR]