Multiple national efforts focus on eliminating central line–associated bloodstream infections (CLABSIs), which are a key source of patient harm. Prior investigations have shown that although avoidance of these costly infections results in overall health care savings, hospitals may actually earn more from private payer reimbursements for patients that develop CLABSI. This study adapted a historical economic model to estimate the net benefits of preventing CLABSI in Medicare and Medicaid patients in intensive care units. From 1990 to 2008, approximately 50,000 CLABSIs were avoided in these patients, resulting in net savings ranging from $640 million to $1.8 billion for the federal government. This translates into a per dollar rate of return on Centers for Disease Control and Prevention investments between $3.88 and $23.85. These numbers may all be underestimates since only patients in intensive care units were included, and many patients with CLABSI are in other hospital wards. This study provides support for the business case for patient safety efforts.