BACKGROUND: Epidemiological data show substantial variation in the risk of HIV infection between communities within African countries. We hypothesised that focusing appropriate interventions on geographies and key populations at high risk of HIV infection could improve the effect of investments in the HIV response. METHODS: With use of Kenya as a case study, we developed a mathematical model that described the spatiotemporal evolution of the HIV epidemic and that incorporated the demographic, behavioural, and programmatic differences across subnational units. Modelled interventions (male circumcision, behaviour change communication, early antiretoviral therapy, and pre-exposure prophylaxis) could be provided to different population groups according to their risk behaviours or their location. For a given national budget, we compared the effect of a uniform intervention strategy, in which the same complement of interventions is provided across the country, with a focused strategy that tailors the set of interventions and amount of resources allocated to the local epidemiological conditions. FINDINGS: A uniformly distributed combination of HIV prevention interventions could reduce the total number of new HIV infections by 40% during a 15-year period. With no additional spending, this effect could be increased by 14% during the 15 years-almost 100,000 extra infections, and result in 33% fewer new HIV infections occurring every year by the end of the period if the focused approach is used to tailor resource allocation to reflect patterns in local epidemiology. The cumulative difference in new infections during the 15-year projection period depends on total budget and costs of interventions, and could be as great as 150,000 (a cumulative difference as great as 22%) under different assumptions about the unit costs of intervention. INTERPRETATION: The focused approach achieves greater effect than the uniform approach despite exactly the same investment. Through prioritisation of the people and locations at greatest risk of infection, and adaption of the interventions to reflect the local epidemiological context, the focused approach could substantially increase the efficiency and effectiveness of investments in HIV prevention. FUNDING: The Bill & Melinda Gates Foundation and UNAIDS.