By contrast with their outward passage the Wortley Montagus began their homeward journey by sea, admiring the landscapes and antiquities of the Mediterranean shores and islands along the way. But progress in the days of sail, in a naval vessel which had seen better times, was slow, and on reaching Genoa in August 1718 the parents decided to complete their journey overland, leaving their children, then aged respectively six and one, aboard ship with their nurse to face the winter storms of the Bay of Biscay and the English Channel. It was five months before the family was reunited on English soil.

Before leaving Constantinople, Lady Mary had written to Sarah Chiswell announcing her intention of bringing inoculation – ‘this useful invention’ – into fashion in England. A suitable opportunity to begin the campaign might have been the severe epidemic of smallpox that broke out in 1719, shortly after the family's return, but more pressing needs – such as finding somewhere to live – intervened. A further epidemic, only slightly less severe, occurred in 1721 and this time there was no hesitation. In April Maitland, now living in the country near London, was sent for and, in spite of a certain natural reluctance to perform on his home ground under the professional scrutiny of his peers, was prevailed upon to inoculate Edward's young sister Anne, who became the first patient to undergo the operation in England. Important personages, including some of Lady Mary's bêtes noires among the doctors, were privately invited (by one account ‘appointed’) to observe how little she had been incommoded by it – rather less so indeed than her mother, who was soon complaining of being so much harassed by people wanting to learn more about inoculation that she wanted to ‘run into the country to hide myself’. One of the medical witnesses, Dr James Keith, two of whose sons had died of smallpox, was so much impressed by what he saw that he immediately asked Maitland to perform the operation on his only surviving child who had not had smallpox.

It was from one point of view Lady Mary's misfortune to have launched into her crusade – if that is not too strong a word – at a time of sharp division both within the medical profession over other matters, and in court circles at the highest level.