A new study published in theJournal of the American Heart Associationhas found that women patients with culture-negative infective endocarditis (CNIE) had a far worse prognosis than male patients and patients with culture-positive infective endocarditis. This study was conducted by Lanlin Z. and colleagues. Culture-negative infective endocarditis is a formidable challenge in clinical practice, in which the etiological agent cannot be identified by routine blood cultures. Due to the inability to identify the pathogen, it is very difficult to establish proper treatment, with empirical antibiotic therapy being most frequently used, and targeted interventions not being initiated promptly. This situation may lead to increased morbidity and result in poorer outcomes compared with culture-positive cases. A total of 698 patients received surgical treatment for infective endocarditis from the year 2013 to 2024. Of these, 154 (22.1%) were diagnosed with CNIE, while the rest were culture-positive. Researchers compared the baseline characteristics, intraoperative findings, and postoperative outcomes in great detail using multivariate Cox regression and structural equation modeling to identify factors that would affect survival and prognosis. It specifically looked at renal function, cardiac condition, and the need for postoperative RRT, which were considered to be paramount in determining such outcomes. Long-term prognosis by gender was also considered in hopes of finding subgroup-specific patterns that might be useful in future clinical practice. Key Findings The study yielded several important findings that underlined some clinical characteristics and differences in prognosis between CNIE and CPIE patients: Among the 698 patients, 154 (22.1%) were identified as having CNIE. Patients with CNIE had poorer preoperative cardiac and renal function compared with patients with culture-positive infections. The incidence of postoperative RRT was significantly higher in the CNIE group, indicating more severe renal complications after surgery. Overall, there was no significant difference in the long-term survival rates between CNIE and CPIE patients, indicating the equal efficacy of surgical intervention and management in both groups. In contrast, female patients with CNIE had a significantly poorer prognosis, with an HR of 2.13 (95% CI, 1.02–4.43; P = 0.04), indicating a risk of mortality more than doubled compared with others. This large surgical cohort study demonstrated that, while overall survival rates were similar between culture-negative and culture-positive infective endocarditis, female patients with CNIE had a significantly worse prognosis. These findings point to the importance of gender-specific risk assessment and proactive renal management in patients with CNIE.