A clade I monkeypox virus (MPXV) outbreak is ongoing in the Democratic Republic of the Congo; travel-associated clade I MPXV infections have been reported in non-African countries. In November 2024, San Mateo County Health in California identified an electronic laboratory report of polymerase chain reaction results suggestive of clade I MPXV infection in a male traveler who had recently returned from East Africa. After conferring with the California Department of Public Health (CDPH), a county health department worker visited the patient that same day at his home and obtained skin pustule swab specimens for expedited clade I MPXV testing. Clade I MPXV was confirmed the following day by the CDPH Viral and Rickettsial Disease Laboratory. This was the first reported clade I MPXV infection in the Americas. Among 83 identified contacts, five received JYNNEOS vaccine as postexposure prophylaxis. All contacts were monitored for 21 days; no secondary cases were identified. Patients with mpox-compatible lesions or clinical features should receive MPXV testing, and health care providers should immediately notify public health authorities of suspected clade I MPXV infections (e.g., mpox manifestations and travel history to an area with ongoing clade I MPXV transmission) or upon receiving a nonvariola orthopoxvirus DNA detected, clade II MPXV DNA undetectable test result to trigger additional testing and facilitate the rapid implementation of transmission-based precautions and other preventive public health interventions.