Methicillin-resistant Staphylococcus aureus (MRSA) infections are a major cause of human skin and soft tissue infections in the United States.1 MRSA colonization and infection also have been observed in turtles, bats, seals, sheep, rabbits, rodents, cats, dogs, pigs, birds, horses, and cattle,2,3,4,5,6,7,8 and MRSA infections with an epidemiologic link to animal contact have been reported in veterinary personnel, pet owners, and farm animal workers.5,7,8 On January 29, 2008, the County of San Diego Health and Human Services Agency was notified of skin pustules on an African elephant (Loxodonta africana) calf and three of its caretakers at a zoo in San Diego County. After each of these infections (including the calf's infection) was laboratory confirmed as MRSA, an outbreak investigation and response was initiated by the zoo and the agency. This report summarizes the results of that investigation, which identified two additional confirmed MRSA infections, 15 suspected MRSA infections, and three MRSA-colonized persons (all among calf caretakers), and concluded that infection of the elephant calf likely came from a colonized caretaker. This is the first reported case of MRSA in an elephant and of suspected MRSA transmission from an animal to human caretakers at a zoo. Recommendations for preventing MRSA transmission in zoo settings include (1) training employees about their risks for infection and the recommended work practices to reduce them; (2) performing proper hand hygiene before and after animal contact; (3) using personal protective equipment (PPE) when working with ill or infected animals, especially during wound treatment; and (4) cleaning and disinfecting contaminated equipment and surfaces.