Syphilis is a sexually-transmitted disease caused by a bacterium known as a spirochite. The bacterium resides in both the spinal fluid of its human host and if left untreated for long enough, will erode the tissues of the brain, causing insanity and death. Along the way, it produces pain in various parts of the body, notably including the genitals and eyes. The bacterium can be killed with contemporary antibiotic agents such as penicillin, but such techniques were unknown during the Baroque Era. Historically accurate methods of combatting syphilis included the ingestion of mercury, taken either orally or rubbed in to the skin, leading to the aphorism "A night with Venus, a lifetime with Mercury."

The prevalence of the disease is a recurrent topic in the Baroque Cycle, paralleling its dreary recurrence in real-life history. In the Cycle as in history, it is frequently referred to as the "French Pox."

Daniel Waterhouse is told by James II, then the Duke of York, that he suffers from syphilis and has transmitted the disease to his wife and mistress, and through them, to his children (Read more here ). This plants a seed in Daniel's mind that James is both morally and mentally inferior to the task of serving as King and helps motivate Daniel in instigating James' overthrow in the Glorious Revolution.

Jack Shaftoe contracts syphilis after siring his two sons, and seeks treatment from a disreputable French physician while he is dangerously drunk. The physician botches the job, slicing off a portion of Jack's penis with a hot poker, resulting in the vagabond's nickname "Half-Cocked Jack," and producing an inability to perform sexually in the usual fashion.