Spatial analyses of HIV/AIDS related outcomes are growing in popularity as a tool to understand geographic changes in the epidemic and inform the effectiveness of community-based prevention and treatment programs. The Urban Health Study was a serial, cross-sectional epidemiological study of injection drug users (IDUs) in San Francisco between 1987 and 2005 (N = 29,914). HIV testing was conducted for every participant. Participant residence was geocoded to the level of the United States Census tract for every observation in dataset. Local indicator of spatial autocorrelation (LISA) tests were used to identify univariate and bivariate Census tract clusters of HIV positive IDUs in two time periods. We further compared three tract level characteristics (% poverty, % African Americans, and % unemployment) across areas of clustered and non-clustered tracts. We identified significant spatial clustering of high numbers of HIV positive IDUs in the early period (1987-1995) and late period (1996-2005). We found significant bivariate clusters of Census tracts where HIV positive IDUs and tract level poverty were above average compared to the surrounding areas. Our data suggest that poverty, rather than race, was an important neighborhood characteristic associated with the spatial distribution of HIV in SF and its spatial diffusion over time.