The writer reflects on his struggles with ill health, likening his battle with nature to Don Quixote’s quest. He expresses deep appreciation for the recipient’s work, which offers valuable insights, especially on the origins of smallpox and its comparison to leprosy. While acknowledging the superiority of eradication over inoculation, he doubts Europe’s ability to address these health crises collectively. He laments Paris’s poor sanitation and the widespread indifference to meaningful public health reform.

Voltaire notes that he has been seriously ill and close to death, having caught a fever in a hotel he had stayed in. He adds the the Duc de Sulli is leaving his house to take Votlaire to Sulli, but that he will travel instead to Marguerite Madeleine Du Moutier, marquise de Bernières if she would prefer. Voltaire states his desire to go and take care of his health and Henri IV at her home, spending quiet days there. He adds that he hates crowds as much as he loves her so will not mind if she does not have company. He concludes by saying that he has no further news other that the smallpox of Mademoiselle de Sens and the disease of the king of Spain, adding that he wanted to write to his friend Thiériot but does not have the strength.

He begins with information about his childhood, including his godparents, the date of his innoculation against smallpox, and his education; and continues with biographical information about his college years; his first employment; his travels with Thomas Gray; and his Parliamentary activities. Much of the manuscript concerns the pieces he wrote, both published and unpublished, and those he published with the Strawberry Hill Press, as well as his reactions to the reviews he received. He also includes anecdotes concerning his attack by highwaymen in 1749; the family quarrel with his uncle Horace Walpole; and his disagreements with David Hume and Voltaire.

The letter claims that the outbreak of smallpox at Long Ditton was due to the carelessness of common people. It also makes long comments on the writings of Clarendon and Voltaire, states that atheist writings are contemptible, and considers the actions of the Prussian king against British merchants.