In 1655 he resigned his fellowship at All Souls and married Mary Gee in his home village of Wynford Eagle. They had two sons, William (c.1660–1738) and Henry (1668?–1741); another son, James, apparently died young. In 1663 he passed the examinations of the College of Physicians for their licence to practice in Westminster and 6 miles round; but it is probable that he had been settled in London for some time before that. This minimum qualification to practice was the single bond between Sydenham and the College of Physicians throughout the whole of his career.