Background Previous data in infants at risk of the development of atopy demonstrate that neutral prebiotic oligosaccharides (OS) (short chain galacto-OS and long chain fructo-OS, ratio 9 : 1, Immunofortis) reduce the incidence of atopic dermatitis (AD). The aim of this study was to assess the effect of immunologically active OS-supplemented formula feeding on the incidence of early AD in infants at low risk of developing atopy. Methods In this randomised controlled double blind European multicentre trial (seven centres in five countries) 1187 infants without a family history of atopy were recruited. 1130 infants remained in the full analysis set for the intention-to-treat analysis (new prebiotic group: 414; control: 416, breastfeeding reference: 300). AD was diagnosed according to the criteria recommended by the European Task Force on Atopic Dermatitis. Results The cumulative incidence of AD at age 16 weeks was 3.6%, 4.8% and 1.3%, at 24 weeks 4.6%, 7.7% and 3.3% in the new prebiotic, control and reference groups, respectively. At 52 weeks, the cumulative AD incidence was significantly lower in the new prebiotic group (5.6%) than in the control group (9.4%; p = 0.0469), but similar to the reference group (7.0%; ns). AD occurred significantly earlier in the control group than in the new prebiotic group (p = 0.0411). Conclusion This trial indicates a preventive effect of immunoactive OS-supplemented formula feeding on the incidence of early AD in infants at low risk of atopy development. The finding is particularly intriguing because most children with AD in a general population come from low atopy risk strata.