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Background: There is an urgent need to find effective interventions that reduce young South African women’s vulnerability to HIV, and pre-exposure prophylaxis (PrEP) is highly effective when taken consistently. As national programs in Africa launch PrEP programs for young women, it is critical to understand how to effectively create awareness, stimulate interest, and increase uptake of PrEP. Methods: Behavior-centered design (BCD) guided the development of a PrEP social marketing campaign for young women. Ethnographic observations, in-depth interviews, and focus-group discussions with young South African women informed the content and design of a 90-second PrEP demand creation video and two informational brochures. A short survey was administered to young women at their homes after watching a video to evaluate PrEP interest. Of 800 households with a 16-25-year-old female identified from a Cape Town township census, 320 women in these households viewed the video and completed a survey about the video and their interest in PrEP. Results: In focus groups, young women from the township preferred local characters and messaging that was empowering, simple, and motivational. From the household survey of young women who viewed the video, most reported interest in learning more about PrEP (67.7% ‘definitely interested’ and 9.4% ‘somewhat interested’) and taking PrEP (56.4% ‘definitely interested’ and 12.5% ‘somewhat interested’). Factors significantly associated with interest in taking PrEP were having a primary partner with whom they regularly have sex (80.0% vs. 65.2% without a primary partner; adjusted odds ratio (AOR)=3.1, 95% CI: 1.3, 7.0) and being in a sexual partnership for 12 months; AOR=3.0, 95% CI: 1.2, 7.3). Conclusions: A positively framed PrEP demand creation video generated high interest in PrEP among young South African women, particularly among women with a primary partner and a shorter-term relationship. Registration: NCT03142256; registered on 5 May 2017.