Infective endocarditis (IE) is an infection of the inner lining of the heart with high morbidity and mortality despite medical and surgical advancements in recent decades. Hypertrophic cardiomyopathy (HC) is one of several medical conditions that have been linked to an increased risk of IE, but there is a paucity of data on this association. We therefore sought to define the clinical phenotype of IE in patients with HC at a single tertiary care center. A retrospective cohort of 30 adult patients with HC diagnosed with IE between January 1, 2006 and December 31, 2016 at Mayo Clinic Rochester were identified. Similar rates of aortic (n = 14) and mitral (n = 16) valve involvement by IE were noted (47% vs 53%). This finding persisted even in patients with left-ventricular outflow tract obstruction and systolic anterior motion of the mitral valve. Symptomatic embolic complications occurred in 10 cases (33%). Surgical intervention was performed in 11 cases (37%). One-year mortality was remarkably low at 7%. In conclusion, in the largest single-center cohort of IE complicating HC, there were similar rates of both mitral and aortic valve involvement regardless of the presence of left ventricular outflow tract obstruction, which is contrary to a long-standing tenet regarding the association of HC and IE. Moreover, no “high risk” IE subset was identified based on HC-related parameters.