Previous guidelines for endocarditis have suggested repeating blood cultures until they become negative, with limited evidence. Literature reviews were conducted (1) on the incidence of persistent bacteremia and association with outcome and (2) on timing of valve culture negativization to examine the claim for prolongation of antibiotic therapy starting from negative blood cultures. Persistent bacteremia and fever may be present in the first 3 days of endocarditis, despite treatment, and are more common in Staphylococcus (especially MRSA) and Enterococcus species. Persistent bacteremia (48-72 h), persistent infection (day 7), and new onset septic shock are related and predict in-hospital mortality. It is, however, persistent infection at day 7 and septic shock that primarily determine the infectious course of endocarditis, and not persistent bacteremia. Valve cultures at surgery become negative in most cases (>85-90%) after 14-21 days of antibiotic therapy, with no calculated benefit for prolonging therapy after 21 days. Persistent infection at 7 days after appropriate antibiotic therapy is a better key event for prognosis then positive or negative blood cultures at 48-72 h. Therapy prolongation from the day of negative blood cultures is not reasonable. There is no need to survey blood cultures in endocarditis patients after starting therapy.