Techniques of spatial statistics and GIS are applied to socio-economic, demographic and HIV sentinel data to characterize the geographical distribution of HIV prevalence in Zambia and to estimate current prevalence rates. Maps of the 4 years under study (i.e. 1994, 1998, 2002 and 2004) reveal a spatial variation in HIV prevalence with urban and provincial districts having higher prevalence than rural areas. However, there was an overall trend of decrease in HIV prevalence across the country. The year 2004 exhibited the most reduction, coinciding with protective sexual behavior campaigns operating in the country. Risk factors for HIV prevalence included literacy rates, unemployment, poverty and urban residency. Analysis of regression residual maps indicated high spatial autocorrelation: Moran’s I value was 0.28 (z = 4.12 and p < 0.000) and a highly significant Robust LM (lag; p < 0.00000) suggestive of contagious and hierarchic spatial diffusion processes. High HIV prevalence rates among interdependent districts and locational similarity patterns suggest that HIV control programs in the country would require an integrated approach combining HIV prevention messages as well as an understanding of social and cultural interactions between interdependent districts that produce behavioral diffusion of HIV prevalence rates.