Background: Effects of staff provided positive behaviour support (PBS) for individuals with intellectual disabilities are unclear. Method: Using a multicentre non-randomised cluster controlled design, 26 teams of residential group homes, including 245 staff members of 167 individuals with intellectual disabilities, were allocated to a PBS or control group. Conducting multilevel analyses (n = 123) we examined individuals' changes in irritability, other challenging behaviours and quality of life. Results: Compared to controls, irritability did not significantly decrease more in the intervention group, but lethargic behaviours did. Personal development and self-determination significantly increased. Irritability of individuals in the PBS group with higher levels of irritability or lower levels of intellectual disability significantly reduced more compared to controls. Conclusions: PBS was effective in reducing irritability of individuals with severe levels of irritability or intellectual disabilities. Moreover, PBS decreased lethargic behaviours and improved several domains of quality of life.