Background 22q11 deletion syndrome (22q11DS) is associated with mild or borderline intellectual disability (ID). There are hardly any reports on subjects with 22q11DS with moderate or severe ID, and therefore its behavioural and psychiatric characteristics are unknown. Method We describe behavioural and psychiatric characteristics of 33 adults with 22q11DS and a Full‐Scale IQ (FSIQ) below 55. Participants were divided into two groups: one group having a FSIQ ≤ 55 caused by intellectual decline (n = 21) and one group with a FSIQ ≤ 55 who had always functioned at this level (n = 12). Results High scores on psychopathology sub‐scales were found for both subgroups. 22q11DS patients with intellectual decline showed higher rates of co‐morbid psychopathology, particularly psychosis. Furthermore, psychosis and intellectual decline were positive correlated. Conclusion This is the first report addressing adult patients with 22q11DS and moderate to severe ID. Overall we found high levels of psychopathology with higher scores of psychopathology in the intellectual decline group. Life time psychosis seems to be related to deterioration.