Objectives. To evaluate the occurrence of HIV and COVID-19 infections in Philadelphia, Pennsylvania, through July 2020 and identify ecological correlates driving racial disparities in infection incidence. Methods. For each zip code tabulation area, we created citywide comparison Z-score measures of COVID-19 cases, new cases of HIV, and the difference between the scores. Choropleth maps were used to identify areas that were similar or dissimilar in terms of disease patterning, and weighted linear regression models helped identify independent ecological predictors of these patterns. Results. Relative to COVID-19, HIV represented a greater burden in Center City Philadelphia, whereas COVID-19 was more apparent in Northeast Philadelphia. Areas with a greater proportion of Black or African American residents were overrepresented in terms of both diseases. Conclusions. Although race is a shared nominal upstream factor that conveys increased risk for both infections, an understanding of separate structural, demographic, and economic risk factors that drive the overrepresentation of COVID-19 cases in racial/ethnic communities across Philadelphia is critical. Public Health Implications. Difference-based measures are useful in identifying areas that are underrepresented or overrepresented with respect to disease occurrence and may be able to elucidate effective or ineffective mitigation strategies. (Am J Public Health. 2022;112(3):408–416. https://doi.org/10.2105/AJPH.2021.306538 )