Background <p>Rotavirus vaccination is widely recommended in infancy and has substantially reduced morbidity from severe gastroenteritis. In premature and medically ill infants, prolonged hospitalization often interferes with timely vaccination. Despite recommendations to vaccinate clinically stable hospitalized infants according to chronological age, concerns regarding adverse events, apnea-bradycardia episodes, and nosocomial transmission continue to limit uptake in neonatal intensive care units (NICUs). Delayed vaccination may result in missed opportunities, as initiation after 24 weeks of age is contraindicated. The objective of this review was to systematically assess the evidence on the administration of rotavirus vaccines to premature and medically ill infants during their in-hospital stay (e.g., neonatal intensive care units or postnatal wards), and to evaluate the occurrence, type, and frequency of adverse events following such vaccination.</p> Methods <p>This systematic review was conducted in accordance with PRISMA guidelines. Medline, Embase, and Web of Science were searched without restrictions on publication year or language. Eligible studies included premature or medically ill infants who received rotavirus vaccination during hospitalization. Randomized controlled trials, cohort studies, case–control studies, and case series with at least five infants were considered. Data were extracted on vaccination uptake, adverse events, viral shedding, and nosocomial infection. Risk of bias was assessed using Joanna Briggs Institute critical appraisal tools, and certainty of evidence was evaluated using the GRADE approach.</p> Results <p>Fifteen observational studies including a total number of 5,443 infants met inclusion criteria; no randomized controlled trials were identified. Vaccination uptake varied widely and was generally low in routine clinical practice. Reported adverse events were predominantly mild and transient, with gastrointestinal symptoms being most common. Fever occurred in up to 10% of vaccinated infants. No cases of intussusception or volvulus were reported. Apnea-bradycardia episodes were inconsistently documented; where assessed, their frequency was comparable to baseline rates or to those observed after routine two-month vaccinations. Viral shedding of vaccine-strain rotavirus was frequently detected, particularly after the first dose; however, nosocomial transmission to unvaccinated infants was rare and not associated with symptomatic gastroenteritis. Overall certainty of evidence was low due to heterogeneity and moderate to high risk of bias.</p> Conclusion <p>Available evidence suggests that in-hospital rotavirus vaccination in clinically stable premature and medically ill infants is generally safe and not associated with relevant nosocomial infection. Nevertheless, uptake remains inconsistent. Standardized protocols, provider education, and implementation-focused strategies are needed to reduce missed vaccination opportunities and ensure timely protection in this high-risk population.</p> Systematic review registration (PROSPERO) <p>CRD420251163827</p>