This study examines the role of the vegetation in catheter induced experimental endocarditis in predisposing to bacterial colonization of cardiac valves and in influencing the course of the disease and response to penicillin therapy. Platelet fibrin vegetations developed at areas of valvular trauma and were colonized when Streptococcus viridans were injected intravenously. Pretreatment with warfarin prevented vegetation formation, but animals still developed endocarditis at the same rate after injection of 106 S. viridans. The course of the disease in anticoagulated animals was more explosive, as determined by a more rapid rise in fever and level of bacteremia. Mean survival was shorter in anticoagulated rabbits (7 versus 12.7 days). Large vegetations containing 109 S. viridans/g were found in control animals, whereas anticoagulated rabbits developed only microscopic deposits. Large vegetations required a longer duration of penicillin therapy to sterilize than the infected valves of the anticoagulated group (7 versus 3 days). Therefore, a preformed platelet fibrin deposit is not a prerequisite for bacterial colonization of cardiac valves. After infection, the vegetation is an important factor in determining the subacute course of disease and resistance to penicillin therapy.