The infant had no history of travel, no history of acute infections in the 3 weeks preceding rash onset, no known immunocompromising conditions, did not attend a child care facility, and had no caregivers outside the home. Within the home, the infant was cared for by four caregivers. Caregiver A acted as the main guardian throughout the infant’s hospital stay and had prolonged exposure with skin-to-skin contact. Caregiver B reported activities that placed him at high risk for monkeypox exposure during the 2 months preceding the infant’s illness (2). Caregiver B reported hematuria and fever, followed by a rash within the 3 weeks before the infant’s symptom onset. One day before the infant became symptomatic, caregiver B moved to another state and sought medical care for his symptoms. He received a positive Orthopoxvirus DNA test result 2 days after the infant’s positive test result, after which, he was lost to follow-up. The infant had daily close contact with caregiver B in the home for 6 weeks before rash onset. Possible routes of transmission included shared bed linens and skin-to-skin contact through holding and daily care activities.