In this article, we report results from the cost analysis of 5 central cancer registries funded by the National Program of Cancer Registries (NPCR). To estimate the true economic costs of operating a cancer registry, we used a cost-assessment tool (CAT) to collect data on all registry activities, not just those funded by the NPCR. Data were collected on actual, rather than budgeted, expenditures, including personnel, consultants, information technology (IT) support, and other factors influencing costs. Factors that can affect registry costs include the amount of consolidation from abstract to incident cases, the method of data reporting, the number of edits that must be performed manually versus electronically, and the amount of interstate data exchange required of a registry. Expenditures were allocated to specific surveillance and data enhancement and analysis activities. Our study confirmed that cost per case varies across registry activities. The cost of surveillance activities per case ranges from $24.79 to $95.78 while the cost of data enhancement and analysis registry activities per reported cancer case ranges from $2.91 to $9.32. Total cost per reported cancer case also varies, ranging from $30 to slightly more than $100, with a median of $45.84. Further research using data from all NPCR-funded registries is required to assess reasons for this variation. Information gained from such an assessment will improve efficiency in registry operations and provide data to better quantify the funding requirements for expanding registry activities.