People with severe mental illness (SMI) experience significantly higher obesity-related comorbidities and premature mortality rates than healthy populations. The physical and social characteristics of neighborhoods where people with SMI reside can play an important role in promoting or hindering healthy eating and physical activity. However, this is seldom considered when designing and testing health behavior interventions for these populations. This study used baseline data from an obesity control trial for low-income, minority people with SMI to demonstrate the utility of assessing neighborhood- and city-level place-based factors within the context of lifestyle interventions. GIS was used to create a zip-code-level social and built environment geodatabase in New York City and Philadelphia, where the trial occurred. Chi-square and t-tests were used to assess differences in the spatial distribution of health-related built and social environment characteristics between and within cities and diet and physical activity outcomes. All types of neighborhood characteristics showed significant environmental differences between and within cities. Several neighborhood characteristics were associated with participants’ baseline healthy eating and physical activity behaviors, emphasizing that place-based factors may moderate lifestyle interventions for SMI patients. Future behavioral interventions targeting place-dependent behaviors should be powered and designed to assess potential moderation by place-based factors.