This paper describes best practices for responding to youth with human immunodeficiency virus (HIV) in the school setting through the application of a school change model designed by the World Health Organization. This model applies a whole school approach and includes four levels that span the continuum from universal prevention to direct intervention. These levels are described and recommendations made, within the context of addressing mental health and educational issues related to HIV prevention and treatment at school. The challenges associated with implementing this model and strategies to overcome these barriers are discussed.