The Louisiana State University Health Care Services Division system assessed the effectiveness of implementing a multisite disease management program targeting diabetes mellitus in an indigent patient population. A population-based disease management program centered on evidence-based clinical care guidelines was applied from the system level. Specific clinic modifications and models were used, as well as ancillary services such as medication assistance and equipment subsidies. Marked improvement in process goals led to improved clinical outcomes. From 2001 to 2008, the percentage of patients with a hemoglobin A1c < 7.0 increased from 45% to 55% on the system level, with some sites experiencing a more dramatic shift. Results were similar across sites, which included both small provider groups and academic health centers. In order to achieve these results, the clinical environment changed to promote those evidence-based interventions. Even in complex environments such as academic health centers with several provider levels, or those environments with limited care resources, disease management programs can be successfully implemented and achieve statistically significant results.