BACKGROUND: Infants with medical risk conditions are vulnerable to childhood infections including acute gastroenteritis (AGE). To guide prevention programs, we quantified AGE incidence, severity and virus prevalence among medical risk infants in the Netherlands. METHODS: This prospective cohort-study was part of the RIVAR-project recruiting infants with prematurity, low birth weight or severe congenital conditions in 13 hospitals. Follow-up included 18 monthly health questionnaires detailing AGE symptoms and healthcare usage. Parents were also instructed to notify when an infant developed AGE, to collect a stool sample and complete a daily severity score (Modified Vesikari Severity). Stool samples were analyzed by real-time polymerase chain reaction for rotavirus, norovirus, adenovirus and astrovirus. RESULTS: Between November 2014 and October 2017, 631 infants participated during 9125 person-months of observation. In total, 559 episodes were identified. The mean AGE incidence rate was 73.5 per 100 person-years (PY) (95% confidence interval: 67.6-79.9) and increased with age [incidence rate: 48.3 (39.8-58.3) vs. 80.2 (73.0-88.1)/100 PY for ages 1-5 vs. 6-18 months, respectively]. Healthcare was attended for 38.1% (213/559) and 26.8% (68/254) were classified as severe based on the Modified Vesikari Severity. Stool samples were obtained from 254 AGE episodes. Norovirus was identified in 65 (25.6%) and rotavirus in 44 (17.7%). Adenovirus and astrovirus together accounted for 8.3% (N = 21). Severe AGE occurred most frequently in rotavirus positive episodes. CONCLUSION: The observed AGE incidence, severity and healthcare usage among medical risk infants confirms substantial disease burden. Norovirus and rotavirus are the dominant pathogens and severe episodes occurred most frequently in children with rotavirus infection. AGE prevention in medical risk infants should be prioritized.