Background: Nowadays, infective endocarditis (IE) is still burdened by a high mortality. In the absence of an adequate prognostic stratification system, it is important to assess new predictors of poor outcomes. The aim of our study is to evaluate which factors were associated with higher mortality in IE patients. Methods: A retrospective cohort study enrolled patients with an IE diagnosis at the Infectious Diseases Clinic of the University ‘G. D’Annunzio’, Chieti, Italy from January 2013 to December 2019. For each patient, demographic, anamnestic and clinical information, embolic phenomena, laboratory and microbiologic data, treatment, and outcomes were collected and analyzed. A correlation analysis was performed. Results: Sixty-eight patients with EI were studied; among them, the mortality was 17.6%, 20.6%, and 23.5%, intra-hospital, at 1 month from discharge and at 6 months from discharge, respectively. Mortality was significantly correlated with age, estimated glomerular filtration rate, and procalcitonin values when considering either basal values (r = 0.266, p = 0.029), or values at 48–72 h from the start of an antibiotic therapy (r = 0.222; p < 0.05), cerebral embolization for 6-month mortality (r = 0.284; p = 0.019), and inadequate antibiotic therapy (r = 0.232, p < 0.05). Conclusions: Procalcitonin values, at EI diagnosis and at 48–72 h after starting antibiotics, are prognostic factors useful for stratifying patient risk, and for setting up a personalized treatment. Of note, cerebral embolization and an inappropriate empirical treatment were associated with a higher mortality in the short- and long-term.