By 1658 Sydenham, who had fought on the parliamentary side during the English Civil War, was living in the eastern end of the new neighbourhood of Pall Mall. Despite only holding a BM he identified himself as a physician. In 1663 he became a licentiate of the College of Physicians and therefore continued to practice, although he did not obtain his MD until 1676.

Sydenham was a talented clinician and he was particularly noted for his ability to make fine distinctions between diseases. Sydenham’s most important work was his 'Observationes medicae' (1676) which focused on epidemic diseases and their origins. Overall, Sydenham’s work was significant in encouraging the growth of nosology.