The aim of the current study is to examine the quality of sibling relationship in families with a sibling with substance misuse (SSU) and compare the relationship to families with a sibling with no use (SNU). Thirty-six (36) families participated in the study (17 with SSU and 19 with SNU; N = 144). Semi-structured interviews were conducted with 40 siblings (20 SNU and 20 SSU; 18-31 years old) in order to qualitatively investigate the characteristics of the sibling relationship. The siblings were not identified with any psychopathology, according to SCL-90R. Moreover, we considered the family cohesion and adaptability, as identified by the FACES III (administered to the whole sample) and the family constellation (including number of children, birth order, gender, family size, family structure, years of substance misuse and socioeconomic level). The results of the thematic analysis seem to support Furman and Buhrmester’s (1985) framework, in the context of SNU families. Nevertheless, when considering families with SSU the framework is enriched with a new axis: Loss/mourning. The substance misuse seems to provoke an overturn of the representation of the sibling relationship: the behavioral changes (i.e. disengagement) of the sibling with drug use are experienced as a loss by the sibling non user, thus triggering the psychological process of ‘mourning’. Moreover, in these families, the sibling with no drug use seem to experience differential parenting, they feel neglected, angry and they take up a parental role towards the SSU, whom they experience as “sensitive” and “vulnerable”.