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Abstract Background Despite multiple available HIV prevention methods, the HIV epidemic continues to affect South Africa the most. We sought to understand willingness to use actual and hypothetical HIV prevention methods among participants enrolled in a preventative HIV vaccine efficacy trial in Soweto, South Africa. Methods We conducted a qualitative study with 38 self-reporting HIV-uninfected and consenting 18–35 year olds participating in the HVTN 702 vaccine efficacy trial in Soweto. Using a semi-structured interview guide, five focus group discussions (FGDs) were held, stratified by age, gender and sexual orientation. The FGDs were composed of: (i) 10 heterosexual women aged 18–24 years; (ii) 9 heterosexual and bisexual women aged 25–35 years; (iii & iv) heterosexual men aged 25–35 years with 7 in both groups; and (v) 5 men aged 18–35 years who have sex with men. FGDs were audio-recorded, transcribed verbatim, translated into English and analysed using thematic analysis. Results We present five main themes: (i) long-lasting methods are preferable; (ii) condoms are well-known but not preferred for use; (iii) administration route of HIV prevention method is a consideration for the user; (iv) ideal HIV prevention methods should blend into the lifestyle of the user; and the perception that (v) visible prevention methods indicate sexual indiscretion. Conclusions The participants’ candour about barriers to condom and daily oral pre-exposure prophylaxis (PrEP) use, and expressed preferences for long-lasting, discreet, lifestyle-friendly methods reveal a gap in the biomedical prevention market aiming to reduce sexually acquired HIV in South Africa. Product developers should consider long-acting injectable formulations, such as vaccines, passive antibodies and chemoprophylaxis, for HIV prevention technologies. Future innovations in HIV prevention products may need to address the desire for the method to blend easily into lifestyles, such as food-medication formulations.