HIV/AIDS prevalence remains a major global public health and development challenge despite key interventions to curb its spread. Ghana, in particular, for a decade now, has experienced a persistent increase in the number of HIV new infections among adults, with the new infection rates varying across the administrative regions. The study examines socio-demographic, health, social, behavioural, and biomedical factors contributing to the spread of HIV among adults in Ghana and how these factors vary across administrative regions. A case-control study was carried on involving 362 respondents made of 181 HIV cases and controls, each from the Ahafo and Northern regions of Ghana. Structured questionnaires were administered. Socio-demographic characteristics of respondents, their health status, social behavioural, and biomedical factors that have potential influence on the spread of HIV was collected. A logistic regression model was used to estimate the degree to which each of the risk factors collected were associated with the spread of HIV in Ghana and across regions. Out of 21 risk factors identified, 13 accounted for the spread of HIV in the Ahafo region compared to only 6 in the Northern region. The study concludes that factors for HIV spread in Ghana are many but vary across administrative regions in the country. It, therefore, suggests the need to create job opportunities, have HIV awareness campaign programmes, regulate the sale of alcoholic and other related drugs, discourage sex trade, promote condom use throughout the country for those who cannot abstain, and tailored to regions. Keywords: Adults, Biomedical Factors, HIV Spread, Socio-Behavioural.