The Comarca Ngäbe-Buglé, an administratively autonomous Indigenous region in western Panama, is home to a significant population rural Indigenous people of Ngäbe and Buglé ethnicity. HIV prevalence in the Comarca is two times higher than the national average, and the great majority of cases are concentrated in young men. Yet, there is little data regarding socio-cultural and sexual behaviour factors that may drive this high prevalence. Understanding such factors would enable the development of relevant prevention interventions. We conducted a qualitative study between January and March 2018, consisting of 20 semi-structured interviews with male and female young people aged 14-19 years, complemented with ethnographic observations of one month's duration each in two communities within the Comarca, to identify potential factors that could increase risk of HIV and other sexually transmitted infections (STIs). We suggest that interventions to prevent HIV and other STIs should focus on increasing open communication between sex partners, especially with respect to condom use, as well as facilitating people-driven change in gender norms that are harmful to both young women and young men.