Among all the diseases and pathologies of the twentieth and twenty-first centuries, HIV infection/AIDS is possibly one of the most stigmatized, overtaking other ancient diseases that were stigmatized in the past such as epilepsy, leprosy, or the plague. The stigma faced by people living with HIV is multiple and cumulative because it combines various factors of being a transmissible infection that causes fear in others, that its transmission routes are mostly related to sexuality and drugs, and also having especially affected in the early days already stigmatized groups such as drug addicts, men who have sex with other men (as represented by the expression “gay plague” from the 80 s), or people who engage in sex work. Obviously, this stigma, both when it is external generates discrimination and fear of rejection, and when it is internalized, has lethal consequences for the physical and mental health of those living with HIV who are drug-dependent. And this obliges us to promote preventive community interventions to reduce this stigma, as well as individual or group psychological interventions when the infection is already present in the individual who suffers its devastating effects. This chapter will address all these issues from a historical, biopsychosocial, and proactive perspective, proposing possible lines of action to address this problem.