To test the hypothesis that heart rate characteristic (HRC) monitoring adds information to clinical signs of illness in diagnosing neonatal sepsis, we prospectively recorded clinical data and the HRC index in 76 episodes of proven sepsis and 80 episodes of clinical sepsis in 337 infants in the University of Virginia NICU more than 7 d old. We devised an illness severity score based on clinical findings and tests relevant to sepsis. Point scores were derived from coefficients of multivariable regression models, and we internally validated a total score. We determined relationships of the HRC index with individual clinical signs, laboratory tests, and the total score. We found highly significant correlations of the clinical score and individual clinical signs with the HRC index. The clinical score and HRC index added independent information in predicting sepsis, and were similar in clinical and proven sepsis. The clinical score and the HRC index rose before sepsis, and the HRC index rose first. We conclude that clinical signs of illness and HRC monitoring add independent information to one another in the diagnosis of neonatal sepsis.