In August 1906, Mallon took a position in Oyster Bay on Long Island with the family of a wealthy New York banker, Charles Henry Warren. Mallon went along with the Warrens when they rented a house in Oyster Bay for the summer of 1906. From August 27 to September 3, six of the 11 people in the family came down with typhoid fever. The disease at that time was "unusual" in Oyster Bay, according to three medical doctors who practiced there. The landlord, understanding that it would be impossible to rent a house with the reputation of typhoid, hired several independent experts to find the source of infection. They took water samples from pipes, faucets, toilets, and the cesspool, all of which were negative for typhoid.
In late 1906, Mallon was hired by Walter Bowen, whose family lived on Park Avenue. Their maid got sick on January 23, 1907, and soon Charles Warren’s only daughter got typhoid and died. This case helped to identify Mallon as the source of the infections. George Soper, an investigator hired by Warren after the outbreak in Oyster Bay, had been trying to determine the cause of typhoid outbreaks in well-to-do families, when it was known that the disease typically struck in unsanitary environments. He discovered that a female Irish cook, who fitted the physical description he had been given, was involved in all of the outbreaks. He was unable to locate her because she generally left after an outbreak began, without giving a forwarding address. Soper then learned of an active outbreak in a penthouse on Park Avenue and discovered Mallon was the cook. Two of the household's servants were hospitalized, and the daughter of the family died of typhoid.