Introduction: Adults with intellectual disabilities have an increased vulnerability to mental health problems and challenging behaviour. In addition to psychotherapeutic or psychoeducational methods, off-label pharmacotherapy, is a commonly used treatment modality. Objective: The aim of this study was to establish evidence-based guideline recommendations for the responsible prescription of off-label psychotropic drugs, in relation to Quality of Life (QoL). Method: A list of guidelines was selected, and principles were established based on international literature, guideline review and expert evaluation. The Delphi method was used to achieve consensus about guideline recommendations among a 58-member international multidisciplinary expert Delphi panel. Thirty-three statements were rated on a 5-point Likert-scale, ranging from totally disagree to totally agree, in consecutive Delphi rounds. When at least 70% of the participants agreed (score equal or higher than 4), a statement was accepted . Statements without a consensus were adjusted between consecutive Delphi rounds based on feedback from the Delphi panel. Results: Consensus was reached on 4 general:the importance of non-pharmaceutical treatments, comprehensive diagnostics and multidisciplinary treatment. Consensus was reached in 4 rounds on 29 statements. No consensus was reached on 4 statements concerning: freedom-restricting measures, the treatment plan, the evaluation of the treatment plan, and the informed consent. Conclusion: The study led to recommendations and principles for the responsible prescription -- aligned with the QoL perspective -- of off-label psychotropic drugs for adults with intellectual disabilities and challenging behaviour. Extensive discussion is needed regarding the issues on which there was no consensus to furthering the ongoing development of this guideline.