Comprehensive sexuality education (CSE) is recognised as an effective method of sexual health education, with the school identified as a fitting site of implementation. Its holistic and participatory nature endeavours to develop the knowledge, attitudes and life-skills of students to help them secure their sexual and reproductive health and rights (SRHR). This qualitative study aimed to better understand aspects of CSE implementation in one context. Specifically, it focuses on the effects of the cultural setting, considering how gender and sexuality norms influence teacher and student implementation strategies. The research was carried out in one secondary school in Ethiopia, which delivered a Dutch-developed programme throughout 2013. Over 50 in-depth interviews were conducted with teachers and students, influential community members and experts in SRHR. Data were also gathered through focus group discussions and classroom observations. Results show that CSE teachers and students, both male and female, were able to discuss issues of sexuality. However, the cultural context was seen to affect interpretation of programme information, influencing the nature of this discussion. For an impactful implementation, it is recommended that sexuality education aims to engage with and involve the wider community, to reduce contradictory messages and increase programme support. Furthermore, teachers should undergo extensive and comprehensive pre-programme training that addresses their attitudes and values, not just their knowledge.