Background: Sexual behaviour and sexually transmitted infections are strongly affected by social connections, and interventions are often adapted more readily when diffused through social networks. However, evidence on how young people acquire ideas and change behaviour through the influence of important social contacts is not well understood in high-HIV-prevalence settings, with the result that past peer-led HIV-prevention interventions have had limited success. Methods: We therefore designed a cohort study (named Sixhumene or ‘we are connected’) to follow young people in three rural and small-town communities in uMkhanyakude district, KwaZulu-Natal, South Africa, and the people that these youth identify as important in their lives. We will interview them five times over three years, at each visit collecting information on their socioeconomic, social and sexual health lives, and testing them for HIV and herpes simplex virus 2 (HSV-2). We will use this information to understand how these young people’s sexual health decisions are formed. This will include evaluating how poor sexual health outcomes are correlated across social networks, how youth mimic the attitudes and behaviours of those around them, who is at greatest risk of acquiring HIV and HSV-2, and who might be most influential within communities and thus best able to promote protective interventions. Discussion: The information gathered through this study will allow us to describe social connection and influence spread through these real-world social networks, and how this leads to sexual health outcomes. Sixhumene will provide vital inputs for mathematical models of communities and spreading processes, as well as inform the development of effective interventions to protect the sexual health of community members through appropriate targeting with optimised messaging requiring fewer resources.