Background Limited research exists on pre-exposure prophylaxis (PrEP) interest or use among female university students in high HIV-prevalence African settings. This study sought to establish the relationship between epidemiologic and perceived HIV risk and PrEP intention among Zambian female university students. Methods We recruited female students at an urban university to complete a survey on intention to use PrEP in the next year (primary outcome); other PrEP knowledge, attitudes, and behaviors; demographics; epidemiologic HIV risk and risk perception. Descriptive statistics, regression and mediation analyses were used. Results Of the 454 sexually active participants, 118 (26%) reported PrEP intention. Actual PrEP use was rare (< 5%). The odds of PrEP intention increased for those with perceived high HIV risk (aOR 3.08; 95% CI 1.71-5.55) and with each year at university (aOR 1.47; 95% CI 1.21-1.80) but decreased with higher PrEP stigma (aOR 0.91; 95% CI 0.86-0.96) and more negative PrEP perceptions (aOR 0.91; 95% CI 0.85-0.97). More epidemiologic risk factors were originally associated with PrEP intention (OR 1.24; 95% CI 1.01-1.53 for each risk factor), though this relationship weakened after adjustment for perceived HIV risk, which mediated 69% of the relationship between epidemiologic HIV risk and PrEP intention. Only 29% of high-risk participants recognized their high epidemiological HIV risk (3+ risk factors). Conclusions Along with PrEP education and stigma reduction, there is a need for approaches that help female university students in Zambia accurately identify their HIV risk to make informed PrEP decisions.