Background: Homelessness is one of the most severe forms of social exclusion. It is characterized by processes of weakening of interpersonal bonds, being considered an important public health issue. The objective of this study is to elucidate how the interpersonal relationships changed over the life cycle of homeless drug and alcohol users. Method: We used the qualitative methodology. The participants were adults who had a history of homelessness and use of alcohol and other drugs at some point. The interviews were semi structured and used the timeline instrument. All of them were fully recorded, transcribed, and submitted to Thematic Analysis.Results: Twenty individuals participated in the study. Reports on social exclusion over time stood out in four large themes and their respective subthemes. Theme 1 – Childhood: participants reported instability in their upbringing, abuse, and violence, and regarded their father figure as not very present or absent. Theme 2 – Adolescence: school dropout and failure; acceptance of gender and sexual orientation; birth of first child, living together or getting married prevailed. Theme 3 – Adulthood: estrangement or conflicting relationship with family; health problems; drug trafficking and prostitution. Theme 4 – Cross-cutting factors: death of relatives and substance use. Conclusion: The results suggest that these interpersonal relationships are permeated by successive breakups, conflicts and other events that pile up over time, may start in childhood and cross the subsequent phases. Substance abuse and dependence are mentioned as cross-cutting factors that intensify social exclusion in all the phases of the life cycle.