Mackenzie, the leading throat specialist of the time, was called into the difficult case of the German crown prince Frederick in May 1887. Frederick's illness had been diagnosed by German physicians as throat cancer. Basing his opinion on a biopsy made by the eminent German pathologist Rudolf Virchow, Mackenzie insisted that the throat lesion was not demonstrably cancerous and that an operation was unnecessary.

Mackenzie was knighted in September 1887 and decorated with the Grand Cross of the Hohenzollern Order the following year. By November, however, the disease was confirmed to be cancer. Frederick became emperor on March 9, 1888, and died on June 15. A heated dispute erupted between Mackenzie and the German doctors. After a critical account of the case was published in Germany, Mackenzie retaliated with The Fatal Illness of Frederick the Noble (1888), for which he was censured by the Royal College of Surgeons.