Coagulase-negative staphylococcal species are generally considered commensal inhabitants of the skin. Often regarded as avirulent organisms, certain species such as Staphylococcus lugdunensis have been identified as the cause of severe human infections including infective endocarditis. We report on a case of a native valve, S. lugdunensis infective endocarditis relapse after initial conservative medical therapy. A literature review of the outcomes of treatment was also performed. Analyzing definitive medical versus medical-surgical treatment of native valve infective endocarditis, an odds ratio of mortality of 3.1875 (95% confidence interval [CI], 1.1855-8.5705; P < 0.03) was obtained and was significant based on 2-tailed Fisher exact probability test. This analysis reveals an increase risk of mortality with medical therapy alone versus medical-surgical therapy for native valve infective endocarditis. Our case and review of the literature emphasize the growing evidence that early medical treatment and surgical evaluation and removal of infected foreign hardware is required to prevent significant morbidity and mortality.