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Abstract Background The World Health Organization recommends Pre-Exposure Prophylaxis (PrEP) for all populations at substantial risk of HIV infection. Understanding PrEP awareness and interest is crucial for designing PrEP programs; however, data are lacking in sub-Saharan Africa. In Malawi, oral PrEP was introduced in 2018. We analyzed data from the 2020 Malawi Population-based HIV Impact Assessment (MPHIA) to assess PrEP awareness and factors associated with PrEP interest in Malawi. Methods MPHIA 2020 was a national cross-sectional household-based survey targeting adults aged 15 + years. Oral PrEP was first described to the survey participants as taking a daily pill to reduce the chance of getting HIV. To assess awareness, participants were asked if they had ever heard of PrEP and to assess interest, were asked if they would take PrEP to prevent HIV, regardless of previous PrEP knowledge. Only sexually active HIV-negative participants are included in this analysis. We used multivariable logistic regression to assess sociodemographic factors and behaviors associated with PrEP interest. All results were weighted. Results We included 13,995 HIV-negative sexually active participants; median age was 29 years old. Overall, 15.0%, 95% confidence interval (CI): 14.2–15.9% of participants were aware of PrEP. More males (adjusted odds ratio (aOR): 1.3, 95% CI: 1.2–1.5), those with secondary (aOR: 1.5, 95% CI: 1.2-2.0) or post-secondary (aOR: 3.4, 95% CI: 2.4–4.9) education and the wealthiest (aOR: 1.6, 95% CI: 1.2-2.0) were aware of PrEP than female, those without education and least wealthy participants, respectively. Overall, 73.0% (95% CI: 71.8–74.1%) of participants were willing to use PrEP. Being male (aOR: 1.2; 95% CI: 1.1–1.3) and having more than one sexual partner (aOR: 1.7 95% CI: 1.4–1.9), were associated higher willingness to use PrEP. Conclusions In this survey, prior PrEP knowledge and use were low while PrEP interest was high. High risk sexual behavior was associated with willingness to use PrEP. Strategies to increase PrEP awareness and universal access, may reduce HIV transmission.