Clinical manifestations of infective endocarditis (IE) can be highly non-specific. Our objective was to describe the clinical characteristics of patients initially referred to a department of internal medicine for a diagnostic work-up, and eventually diagnosed with IE. We retrospectively retrieved adult patients admitted to the department of internal medicine at Lille University Hospital between 2004 and 2015 who fulfilled Duke Classification criteria for definite IE. Thirty-five patients were included. The most frequently involved bacteria were non-hemolytic streptococci. Most patients presented with various systemic, cardiac, embolic, rheumatic, and immunological findings, with no sign or symptom displaying high sensitivity. The first transthoracic echocardiogram was negative in 42% of patients. Furthermore, definite diagnosis required performing at least 2 transesophageal examinations in 24% of patients. We observed a trend towards decreased survival in the subgroup of patients in whom the delay between onset of symptoms and diagnosis was >30 days. In conclusion, patients who are initially referred to internal medicine for a diagnosis work-up and who are ultimately diagnosed with IE have non-specific symptoms and a high percentage of initial normal echocardiography. Those patients require prolonged echocardiographic monitoring as a prolonged delay in diagnosis is associated with poorer outcomes such as death.