<p>HIV cluster detection and response (CDR) provides a framework for identifying rapid HIV transmission and guiding implementation of proven HIV prevention and care strategies. Characterizing the relative benefits of CDR is important for guiding policy makers in resource allocation for HIV prevention. We sought to understand how many HIV infections would need to be averted by CDR activities to achieve various return-on-investment (ROI) thresholds. We conducted an ROI analysis of CDR in 2022, incorporating costs and benefits across US jurisdictions funded for HIV surveillance and prevention. Setting ROI thresholds between 1 and 5, we estimated the number of HIV infections that would need to be averted annually by CDR activities to reach ROI thresholds. A scenario was considered cost saving if the ROI &gt; 1. Based on the number of people in national priority molecular clusters and estimated transmission in these clusters, we determined the percent reduction in transmission within these clusters that would be required to achieve the threshold number of HIV infections averted. The number of HIV infections needing to be averted annually ranged from 19 infections (ROI = 1) to 94 infections (ROI = 5). Among 657 HIV transmissions within national priority molecular clusters, the percent reduction in HIV transmission needed to meet ROI thresholds ranged from 2.9% (ROI = 1) to 14.3% (ROI = 5). In conclusion, CDR activities would need to avert a minimal number of HIV infections nationally to achieve cost savings.</p>