She defied convention most memorably with her pioneering of a smallpox inoculation, a course of action unparalleled in medical advance up to that point. Lady Mary's own brother had died of smallpox and her own famous beauty had been marred by a bout with the disease in 1715. In 1717, she went to live in Turkey with her husband, the British ambassador to that country, and stayed for two years. In the Ottoman Empire, she visited the women in their segregated zenanas, learning Turkish, making friends and learning about Turkish customs. There she witnessed the practice of inoculation against smallpox—variolation—which she called engrafting, and wrote home about it. Variolation used live smallpox virus in the liquid taken from a smallpox blister in a mild case of the disease and carried in a nutshell. Lady Mary was eager to spare her children, and had her son inoculated while in Turkey. On her return to London, she enthusiastically promoted the procedure, but encountered a great deal of resistance from the medical establishment, because it was an "Oriental" process.
Emanuel Timoni, a Greek physician who also attended the Wortley Montagues, had also described the procedure a few years earlier. Dr. Timoni first described this procedure in the Philosophical Transactions of the Royal Society of London in 1714. James Pylarini described it again in the Transactions in 1716. They called it variolation (varus is Latin for pimple) or inoculation (inoculare means to graft).
In 1721, after a smallpox epidemic struck England, she had her three-year-old daughter inoculated by Charles Maitland, a physician who had been at the embassy in Turkey, and publicized the event. She persuaded Princess Caroline to test the treatment. Seven prisoners awaiting execution were offered the chance to undergo variolation instead of execution: they all survived and were released. Then six orphan children were inoculated: they all survived. In 1722 King George I allowed Maitland to inoculate two of his grandchildren, children of the Princess. The children recovered.
However, in another household, six servants became ill with smallpox after a child was inoculated. Some clergymen then announced that trying to prevent the illness was against God's will. Some physicians warned that inoculation might spread the disease. Nevertheless, inoculation became known as a way to prevent smallpox. In fact, using live virus did carry a risk of infection. About 3% of those inoculated developed smallpox and died. Others spent weeks recovering. However, that was preferable to catching smallpox in the wild, with its mortality rate of 20–40% and survivors left scarred and sometimes blind.
In response to the fear of inoculation, Lady Mary wrote an anonymous article describing inoculation as it was practised in Turkey. Inoculation gained general acceptance. In 1754 she was praised for bringing the practice to Britain.
In later years, Edward Jenner, who was 13 years old when Lady Mary died, developed the much safer technique of vaccination using cowpox instead of smallpox. As vaccination gained acceptance, variolation gradually fell out of favour.