We aimed to estimate the individual and joint impact of age, marital status and diagnosis with sexually transmitted infections (STIs) on HIV acquisition among young women at a population level in Durban, KwaZulu-Natal, South Africa. A total of 3,978 HIV seronegative women were recruited for four biomedical intervention trials from 2002–2009. Point and interval estimates of partial population attributable risk (PAR) were used to quantify the proportion of HIV seroconversions which can be prevented if a combination of risk factors is eliminated from a target population. More than 70% of the observed HIV acquisitions were collectively attributed to the three risk factors: younger age (<25 years old), unmarried and not cohabiting with a stable/regular partner and diagnosis with STIs. Addressing these risks requires targeted structural, behavioural, biomedical and cultural interventions in order to impact on unacceptably high HIV incidence rates among young women and the population as a whole.