Background People with intellectual disabilities are vulnerable to develop psychopathology (in particular anxiety) and related challenging behaviour. A diagnostic guideline was developed to support professionals to better diagnose and thus treat psychopathology and related CB. This study examined preliminary outcomes from the application of this guideline. Method A comparative multiple case study with an experimental and a control condition. Results The application of the guideline showed a trend of decreases of internalizing problems (P = 0.07) and anxiety/depressed problems (P = 0.09). We found no statistically significant decreases of externalizing problems and no increases in perceived quality of life as compared with care as usual. Clients were not more satisfied with the support they received for coping with their emotional and behaviour problems. Conclusion The application of the Diagnostic Guideline for Anxiety and Challenging Behaviour did not show statistically significant changes in externalizing problems and Quality of Life. Despite the small sample size of n = 59, we did find a trend in decreasing internalizing problems and anxiety/depressed problems. Further research into either or not confirming these trends is recommended.