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As an interface between health and education, comprehensive sexuality education (CSE) offers a potent tool among other interventions to accelerate healthy transition of adolescents into adulthood. With increasing interest in in-school CSE provision/delivery, young people in out-of-school contexts may be left behind. This study forms part of implementation research to understand if the activities used to train and support the facilitators are feasible, appropriate, acceptable, and effective in enabling them to engage a defined group of young people, deliver CSE to them in the out-of-school context, and assist them in obtaining relevant services. This paper presents findings of mapping of out-of-school CSE interventions in Ghana, ongoing or completed between 2015 and 2020, and then discusses a needs assessment of two purposively selected groups of vulnerable out-of-school youth: young people living with HIV and AIDS (YPLHIV) and those living in detention (YPiD). We conducted 10 interviews with YPLHIV and three focus group discussions with YPiD in November 2020. Qualitative data were analysed thematically using both deductive and inductive approaches. The mapping yielded 29 interventions (18/62% were ongoing) focused extensively on the delivery of CSE-related knowledge and information; none were aimed at building facilitators' capacity and most targeted the northern regions. Among YPLHIV, living positively after diagnosis, disclosure skills and use of HIV/AIDS health services were critical. YpID sought clarification on personal hygiene, consent in sexual relationships, medium/channel to deliver CSE, and issues around same-sex sexual intercourse. Both groups sought skills in dealing with stigmatisation and discrimination. Implications of the findings for our own and other interventions are highlighted. [ABSTRACT FROM AUTHOR]