BACKGROUND: Clusters of rapid HIV transmission indicate larger underlying networks that are not effectively reached by HIV prevention, testing, and care services. Starting in 2018, the Centers for Disease Control and Prevention (CDC) funded 59 U.S. health departments (HDs) to detect and respond to HIV clusters; HDs began reporting clusters to CDC in January 2020. METHODS: For clusters reported to CDC, we described cluster characteristics at detection, including detection method; size; HIV transmission category, defined as that of >50% of cluster members; and HD investigation and response activities. RESULTS: During 2020-2022, 45 HDs reported 322 HIV clusters, with most detected by molecular analysis of HIV sequences (75%). Most were detected in the South (46%) and three-quarters were predominant sexual transmission. Median cluster size at detection for molecular clusters was 10 persons (interquartile range 7-18). Among 205 clusters with follow-up data, investigation and response activities were conducted for 95%, including direct outreach to persons in clusters for partner services (64%), medical chart reviews (42%), and focused testing events (13%). Limited data on named partners tested showed that 11% received new HIV diagnoses. CONCLUSIONS: HD HIV cluster detection activities detected many clusters. Response activities were tailored for different clusters and intervened in networks with rapid transmission and high undiagnosed infection, as indicated by high positivity among partners. Cluster detection and response is an important tool to identify and address gaps in HIV prevention, testing, and care that facilitate rapid transmission.