Background: Current microbicide clinical trials primarily enroll adult participants; however, females under the age of 18, because of their high rates of HIV acquisition, represent an important population for future microbicide clinical research. We sought to understand the individual, family and community-level factors that may influence the acceptability of microbicide use and research involving adolescent girls. Methods: We conducted 30 interviews with adolescent girls aged 14–17 and nine focus group discussions with adolescent girls, parents and community leaders in Kisumu, Kenya. Participants discussed adolescent sexuality, HIV prevention methods, perceptions about microbicide use and views about microbicide research involving adolescent girls. Results: Adolescent sexual activity is stigmatised yet acknowledged to be a natural part of the ‘adolescent stage.’ Desperation to stop the spread of HIV among youth and support for female-initiated HIV prevention methods led to enthusiasm about microbicides and future microbicide research. Yet concerns about microbicides were numerous and included: difficulty using it in a timely manner due to the rushed, unplanned nature of adolescent sex; a fear of trying experimental products; concerns about microbicide efficacy; and parental worry that supporting microbicide use in youth would defy societal pressures that denounce adolescent sexual activity. Conclusions: Microbicide acceptability for youth in sub-Saharan Africa may be bolstered by desperation for new methods to stop the spread of HIV, yet hindered by misgivings about experimental HIV prevention methods for youth. Understanding and addressing the microbicide’s perceived benefits and shortcomings, as well as the broader context of adolescent sexuality and HIV prevention, may facilitate future research and promotion of microbicides in this high-risk group.