Core Tip: The present report describes a case of vancomycin-induced thrombocytopenia (VIT) in endocarditis and reviews all VIT cases reported in the literature, in terms of indications, diagnosis, management, and potential molecular mechanisms. The present case highlights the importance of accurate diagnosis of VIT in endocarditis, which can be achieved through the time-to-platelet count curve and the Naranjo’s Adverse Drug Reaction Probability Scale score. The platelet count cannot be normalized simply by platelet transfusion alone, and the discontinuation of vancomycin is essential. Due to the anamnestic response to vancomycin re-exposure and the formation of vancomycin-dependent antiplatelet antibodies, the re-administration of vancomycin should be avoided.