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.