The aim of the study was to draw a comparison between the characteristics of infective endocarditis (IE) in patients with cancer and those of IE in noncancer patients.Patients with IE, according to the modified Duke criteria, were prospectively included in the GAMES registry between January 2008 and February 2014 in 30 hospitals. Patients with active cancer were compared with noncancer patients.During the study period, 161 episodes of IE fulfilled the inclusion criteria. We studied 2 populations: patients whose cancer was diagnosed before IE (73.9%) and those whose cancer and IE were diagnosed simultaneously (26.1%). The latter more frequently had community-acquired IE (67.5% vs 26.4%, P < .01), severe sepsis (28.6% vs 11.1%, P = .013), and IE caused by gastrointestinal streptococci (42.9% vs 16.8%, P < .01). However, catheter source (7.1% vs 29.4%, P = .003), invasive procedures (26.2% vs 44.5%, P = .044), and immunosuppressants (9.5% vs 35.6%, P = .002) were less frequent.When compared with noncancer patients, patients with cancer were more often male (75.2% vs 67.7%, P = .049), with a higher comorbidity index (7 vs 4). In addition, IE was more often nosocomial (48.7% vs 29%) and originated in catheters (23.6% vs 6.2%) (all P < .01). Prosthetic endocarditis (21.7% vs 30.3%, P = .022) and surgery when indicated (24.2% vs 46.5%, P < .01) were less common. In-hospital mortality (34.8% vs 25.8%, P = .012) and 1-year mortality (47.8% vs 30.9%, P < .01) were higher in cancer patients, although 30-day mortality was not (24.8% vs 19.3%, P = .087).A significant proportion of cases of IE (5.6%) were recorded in cancer patients, mainly as a consequence of medical interventions. IE may be a harbinger of occult cancer, particularly that of gastrointestinal or urinary origin.