INTRODUCTION: The HIV Prevention 2025 Roadmap, developed by UNAIDS, recommends the adoption of a precision prevention approach focused on priority populations and geographies. With reduction in new HIV acquisitions in many countries, designing a differentiated HIV prevention response, using a Programme Science approach, based on the understanding of the epidemic and transmission dynamics at a sub-national level, is critical. METHODS: To support strategic planning, an epidemic appraisal at the sub-national level across 47 counties, with the 2019 population ranging from 0.14 million in Lamu to 4.40 million in Nairobi City, was conducted in Kenya using several existing data sources. Using 2021 Spectrum/EPP/Naomi model estimates of national and sub-national HIV incidence and prevalence, counties with high HIV incidence and prevalence were identified for geographic prioritization. The size of local key population (KP) networks and HIV prevalence in key and general populations were used to define epidemic typology and prioritize populations for HIV prevention programmes. Analysis of routine programme monitoring data for 2021 was used to assess coverage gaps in HIV prevention programmes, including prevention of vertical transmission, anti-retroviral therapy, KP programmes, adolescent girls and young women programme, and voluntary male medical circumcision programme. RESULTS: Ten counties with more than 1000 incident acquisitions in 2021 accounted for 57% of new acquisitions. Twenty-four counties were grouped into the concentrated epidemic type-due to their low prevalence in the general population, high prevalence in KPs and relatively higher density of female sex workers and men who have sex with men populations. Four counties reflected a generalized epidemic, where HIV prevalence was more than 10% and 30%, respectively, among the general and key populations. The remaining 19 counties were classified as having mixed epidemics. Gaps in programmes were identified and counties where these gaps need to be addressed were also prioritized. CONCLUSIONS: The HIV burden in Kenya is unevenly distributed and hence the mix of prevention strategies may vary according to the epidemic typology of the county. Prioritization of programmes based not only on disease burden and epidemic typology, but also on the prevailing gaps in coverage for reducing inequities is a key aspect of this appraisal.