Infective endocarditis (IE) causes substantial morbidity and mortality if untreated. The clinical course of IE might be different in HIV-positive patients as a result of immune dysfunction. This systematic review investigates the clinical course of IE in HIV-positive compared to HIV-negative patients. A systematic search was performed in PubMed, EMBASE, and Cochrane Library and registered in PROSPERO (CRD42016048649). All articles from 1996 and onward addressing the clinical outcome of HIV-positive adults suffering from IE were reviewed and included based on predefined inclusion and exclusion criteria. A meta-analysis was performed for the outcome mortality. Twenty-three articles were included of which eight included HIVpositive patients only, and 15 compared HIV-positive to HIV-negative patients. Two studies included patients on antiretroviral therapy (ART). HIV and intravenous drug use (IVDU) were closely related. Mortality was higher in HIV-positive patients with a CD4 count below 200 cells/μl than in HIV-positive patients with a higher CD4 count, while mortality was similar for HIV-positive compared to HIV-negative patients (risk ratio = 0.86 [95% confidence interval: 0.53-1.40]). No difference was found in length of hospital stay or rehospitalization. Clinical outcomes were strongly related to the right- or left-sided endocarditis. The clinical course of IE is not different for patients with and without HIV. Clinical outcomes were mainly associated with other factors, such as IVDU and side of cardiac involvement, rather than HIV status.