Introduction Neurodevelopmental disability (ND) represents an adverse condition for infants' socio-emotional and behavioural development as well as for caregiving (eg, parental sensitivity) and mother-infant interaction. Adverse exposures are associated with altered neuroendocrine hormones concentrations (eg, oxytocin and cortisol) and epigenetic regulation (eg, methylation of stress-related genes), which in turn may contribute to less-than-optimal mother-infant interaction. Parental sensitivity is a protective factor for childrens' development and early parental interventions (eg, video-feedback intervention) can promote parental caregiving and better developmental outcomes in children. The present multi-centric and longitudinal randomised controlled trial aims to assess if and to which extent early VFI could benefit both infants and mothers in terms of behavioural outcomes as well as neuroendocrine and epigenetic regulation. Methods and analysis Dyads will be randomly assigned to the video-feedback Intervention Group or Control Group (â € dummy' intervention: telephone calls). Infants with ND aged 3 to 18 months will be recruited from three major child neuropsychiatric units in northern Italy. A multi-layer approach to intervention effects will include videotapes of mother-infant interaction, maternal reports as well as saliva samples for hormones concentrations and target-gene methylation analysis (eg, BDNF, NR3C1, OXTR and SCL6A4) that will be obtained at each of the four assessment sessions: T 0, baseline; T 1, post-intervention; T 2, short-term follow-up (3 month); T 3, long-term follow-up (6 month). Primary effectiveness measures will be infant socio-emotional behaviour and maternal sensitivity. Neuroendocrine hormones concentrations and DNA methylation status of target genes will be secondary outcomes. Feasibility, moderation and confounding variables will be measured and controlled between the two groups. Ethics and dissemination Ethics approval has been obtained in all three participating units. Results of the main trial and each of the secondary endpoints will be submitted for publication in peer-reviewed journals and international conferences. Trial registration number NCT03853564; Pre-results.