Purpose: to identify the main health risk factors of infants participating in a follow-up program. Methods: a longitudinal prospective study conducted with 540 high-risk infants observed in the follow-up clinic of the Hospital Materno Infantil in Goiânia in the State of Goiás, Brazil. All biological data of the infants from birth, prenatal, and postnatal periods were collected through assessment sessions with their mothers and medical chart reviews. Data were analyzed through binary logistic regression to identify the highest-risk variables for the infants’ health. Results: in a predictive analysis, the findings showed that neonatal risk was statistically associated with a lower Apgar score at the fifth minute of life, male infants, and longer hospital stay. Infants with increased neonatal risk were more likely to show alterations identified in cranial ultrasound examinations. Moreover, the longer hospital stay was related to mixed breastfeeding after discharge. Conclusion: the main risk factors for the health of high-risk infants in the follow-up program were: low Apgar score at the fifth minute; male sex; longer hospital stay; alterations detected in transfontanellar ultrasound; and mixed feeding after discharge.