Background: Aggressive behaviour represents a frequent symptom in people with intellectual disability (PWID). Despite uncertain evidence of effectiveness, the use of antipsychotics (APs) drugs to treat aggressive behaviour is very common. Antipsychotic medication of aggressivity in PWID has recently become one of the most debated issues in mental health and the need of further research is persistently stressed by most researchers. Aim: The present study was firstly aimed at evaluating the effectiveness (efficacy on target behaviour, safety and persistence on treatment) of new generation APs, in particular, olanzapine and risperidone in treating aggressive behaviour in PWID for who previous medication with first generation APs (FGAs) were not effective. Methods: 62 subjects with intellectual disability underwent to a 2-arm, parallel group pragmatic trial of olanzapine and risperidone with balanced randomisation and blind assessment of outcome at 4, 8, 12, 16, 20 and 24 weeks after a switch (cross-tapering) from a 24-week treatment with FGAs. Aggressive behaviours were assessed by Overt Aggression Scale (OAS) and clinical outcome by Clinical Global Impression Scale. Side effects were assessed with Dosage Record and Treatment Emergent Symptoms Scale, other symptom-specific scales, laboratory and instrumental tests. Results: Both risperidone and olanzapine resulted to be more effective than FGAs in reducing aggressive behaviour. Repeated-measures analysis of covariance revealed that treatment groups differed for cumulative number of aggressive episodes during the FGAs treatment, which was higher for olanzapine. Conclusion: Our findings seem to confirm that olanzapine and risperidone can be effective in reducing aggressive behaviour in PWID. Both compounds resulted to be well tolerated, with side effects similar to those encountered in other patient populations.