BACKGROUND: Infective endocarditis (IE) is a disease that poses a serious health risk. It is important to identify high-risk patients early in the course of their treatment. In the current study, we evaluated the prognostic value of ultra-short heart-rate variability (HRV), an index of vagal nerve activity, in IE. METHODS: Retrospective analysis was performed on adult patients admitted to a tertiary hospital due to IE. A logistic regression (LR) was used to determine whether clinical, laboratory, and HRV parameters were predictive of specific clinical features (valve type, staphylococcal infection) or severe short-term complications (cardiac, metastatic infection, and death). The accuracy of the model was evaluated through the measurement of the area under the curve (AUC) of the receiver operating characteristic curve (ROC). An analysis of survival was conducted using Cox regression. A number of HRV indices were calculated, including the standard deviation of normal heart-beat intervals (SDNN) and the root mean square of successive differences (RMSSD). RESULTS: 75 patients, aged 60.3(+/-18.6) years old, were examined. When compared with published age- and gender-adjusted HRV norms, SDNN and RMSSD were found to be relatively low in our cohort (75%-76% lower than the median; 33%-41% lower than the 2nd percentile). 26(34.6%) patients developed a metastatic infection, with RMSSD<7.03ms (adjusted odds ratio (aOR) 9.340, p = 0.002), incorporated in a multivariate LR model (AUC 0.833). Furthermore, 27(36.0%) patients were diagnosed with Staphylococcus IE, with SDNN<4.92ms (aOR 5.235, p = 0.004), a major component of the multivariate LR model (AUC 0.741). Multivariate Cox regression survival model, included RMSSD (HR 1.008, p = 0.012). CONCLUSION: SDNN, and particularly RMSSD, derived from ultra-short ECG recordings, may provide prognostic information about patients presenting with IE.