Human milk is recommended as the only alimentary source for the first six months of life. Additionally there is a medical and social need for safe and effective alternative forms of nutrition for infants who cannot be fed with breast milk. Recently the safety and efficacy of some ingredients in infant formulae, such as nucleotides have been discussed. This systematic review analyzed the available evidence to establish the efficacy, safety and dose-response effect of ribonucleotide-supplemented infant formulae (RSIFs). Randomised controlled clinical trials (RCTs) comparing RSIFs to formulae without nucleotides or breast milk were considered in this review. Outcome measures were: antibody titres to common paediatric vaccinations, total lymphocytes, lymphocyte subclasses and NK-cells, episodes of diarrhoea and acute respiratory infection. Publication quality was determined using Jadad and CONSORT guidelines. Results were combined using a random effects model and reported through standardised mean differences (WMD) or risk ratio (RR). Systematic review and meta-analysis showed that RSIFs were associated with a better antibody response to immunisation with Haemopillus influenzae vaccine [SMD 1·74 (99 %CI 1·43–2·05), P = 0·001], diphtheria toxoid [SMD 0·94 (0·75–1·12), P = 0·001], oral polio vaccine [SMD 0·73 (0·51–0·95), P = 0·001], and fewer episodes of diarrhoea [RR 0·67 (0·58–0·76), P = 0·02]. We did not find a major risk of upper respiratory infections [RR 1·11 (0·90–1·36), P = 0·50]. Available evidence suggests a positive benefit of RSFIs on infant health without any risk. These benefits begin with nucleotide addition of 1·9 mg/418·4 kJ and are maintained or increased with 10·78 mg/418·4 kJ.