Background; High-quality, affective relationships are built on meaningful moments of interaction, which are challenging for support staff to establish with people with profound intellectual disabilities. Therefore, we explored what makes a moment of interaction meaningful to support staff and what circumstances facilitate meaningful moments of interaction taking place. Method: Five direct support staff took part in unstructured, in-depth interviews. The interviews were analysed using interpretative phenomenological analysis (IPA). Member checks were also conducted. Results: Support staff experienced moments of interaction as meaningful because they felt a connection with a person with profound intellectual disabilities and/or they had the feeling of being meaningful for this person. Staff-related and contextual circumstances facilitating meaningful moments of interaction to take place were described. Conclusions: Meaningful moments of interaction are highly valued by support staff, who believe these moments are valued by persons with profound intellectual disabilities as well. Implications for daily practice are described.