BACKGROUND: Oral Pre-Exposure Prophylaxis (PrEP) is an effective HIV prevention strategy for adherent users. Adolescent girls and young women (AGYW) in sub-Saharan Africa may particularly benefit from PrEP because of the disproportionate burden of HIV in this group. Understanding potential users' perceptions of and interest in using PrEP is critical to promote the utilization of PrEP by individuals at risk of HIV. METHODS: This qualitative investigation of AGYW's knowledge of and interest in PrEP use was conducted in the context of Girl Power, a quasi-experimental cohort study comparing four models of service delivery at four health centers in Lilongwe, Malawi. We conducted individual in-depth interviews (IDIs) with 40 HIV-negative AGYW ages 15-24 years old six months after enrolment in the parent study. An explanation of PrEP was provided to participants. Interview topics included participants' prior knowledge of, interest in, concerns about, and delivery preferences for PrEP. Analysis consisted of structural coding of interview transcripts corresponding to interview topics, summary of responses within these topics, and identification and description of emerging themes within each topic. RESULTS: None of the AGYW had knowledge of PrEP prior to the IDIs, but once explained, a majority expressed an interest in using it due to inconsistencies in condom use, condom use errors, their own or their partners' concurrent sexual partnerships, and rape. Most AGYW hoped that PrEP would be available in youth-friendly sections of health centers for easy access and youth-friendly counselling. They suggested that discrete packaging of PrEP would be needed to ensure user privacy. Concerns about relationship destabilization and accusations of promiscuity were raised as potential barriers to use. CONCLUSION: General interest in PrEP among AGYW was high. Discrete packaging and access to youth-friendly PrEP delivery modalities may facilitate the utilization of PrEP as a prevention strategy among sexually active AGYW. Attention to potential negative reactions from partners and community members to PrEP use will be needed when introducing PrEP to this population.