The WHO recommends research into non-specific effects of vaccination. For rotavirus vaccines, these have not yet been well established. We studied non-specific effects up to 18 months of age using data from a quasi-experimental before-after study comparing cohorts of rotavirus vaccinated and unvaccinated infants with medical risk conditions.Infants were enrolled at six weeks of age before and after a stepped-wedge implementation of a hospital-based risk-group rotavirus vaccination program. Other infant vaccinations were administered according to the Dutch National Immunization Program and similar in both cohorts. Non-specific effect outcomes were prospectively collected using monthly questionnaires and included acute hospitalization (excluding for acute gastroenteritis), monthly incidence of acute respiratory illness and eczema. We used time-to-event analysis and negative binomial regression to assess the effect of at least one dose of rotavirus vaccination for each of these outcomes. Findings The analysis included 496 rotavirus unvaccinated and 719 vaccinated medical risk infants. In total, 1067 (88%) were premature, 373 (31%) small for gestational age and 201 (17%) had a congenital pathology. The adjusted hazard ratio for first acute hospitalization was 0·91 (95 %CI 0·76;1·16) for rotavirus vaccinated versus unvaccinated infants. Adjusted incidence rate ratio for acute respiratory illness was 1·05 (95 %CI 0·96;1·15) and for eczema 0·89 (95 %CI 0·69;1·15).The results suggest no, or minimal non-specific effects from rotavirus vaccination on acute hospitalization, acute respiratory illness or eczema in medical risk infants.as NTR5361 in the Dutch trial registry, www.trialregister.nl.