Coagulase-negative staphylococci (CoNS) are currently considered typical microorganisms causing infective endocarditis (IE) in patients with prosthetic valves. The objective was to determine variables associated with IE in patients with CoNS bacteremia. We performed an analysis of the clinical characteristics of patients with CoNS bacteremia admitted to a university hospital in Madrid (Spain) from 2021 to December 2022 according to the occurrence of IE. This study is an evaluation of a bacteremia registry. During the study period, 106 patients with CoNS bacteremia were detected. In 85 patients an echocardiogram was performed during hospital admission to rule out IE. Among them, 12 episodes were detected that met IE criteria (14.2%). Of the 6 patients with heart valve prostheses, 5 patients (83.3%) had IE (p < 0.001). Patients with IE more frequently had positive blood cultures more than 12 h after the first draw (58.3% versus 13.4%; p < 0.001). There was a tendency to associate community-acquired bacteremia and to that all blood culture bottles obtained were positive with an increased risk of IE (p = 0.091 and p = 0,057, respectively). Attributable mortality to infection was higher in patients with IE relative to all other patients (16.7% vs. 0%; p = 0.033). The multivariable analysis included having valve prosthesis and persistent bacteremia for more than 12 h. Both were independently associated with IE: valve prosthesis OR 38.6 (95% CI 5.8–258; p < 0.001) and persistent bacteremia OR 2.6 (95% CI 1.1–6.8; p = 0.046). In conclusion, a high percentage of cases of CoNS bacteremia may be due to IE. Some of the variables related to a higher risk of IE, such as having a valvular prosthesis or presenting positive blood cultures for more than 12 h, should lead to rule out or confirm the presence of IE by performing echocardiography.