The Screwtape Letters comprises 31 letters written by a senior demon named Screwtape to his nephew, Wormwood (named after a star in Revelation), a younger and less experienced demon, charged with guiding a man (called "the patient") toward "Our Father Below" (Devil / Satan) from "the Enemy" (God).
After the second letter, the Patient converts to Christianity, and Wormwood is chastised for allowing this. A striking contrast is formed between Wormwood and Screwtape during the rest of the book, wherein Wormwood is depicted through Screwtape's letters as anxious to tempt his patient into extravagantly wicked and deplorable sins, often recklessly, while Screwtape takes a more subtle stance, as in Letter XII wherein he remarks: "... the safest road to hell is the gradual one - the gentle slope, soft underfoot, without sudden turnings, without milestones, without signposts".
In Letter VIII, Screwtape explains to his protégé the different purposes that God and the devils have for the human race: "We want cattle who can finally become food; He wants servants who can finally become sons". With this end in mind, Screwtape urges Wormwood in Letter VI to promote passivity and irresponsibility in the Patient: "(God) wants men to be concerned with what they do; our business is to keep them thinking about what will happen to them".
With his own views on theology, Lewis goes on to describe and discuss sex, love, pride, gluttony, and war in successive letters. Lewis, an Oxford and Cambridge scholar himself, suggests in his work that even intellectuals are not impervious to the influence of such demons, especially during complacent acceptance of the "Historical Point of View" (Letter XXVII).
In Letter XXII, after several attempts to find a licentious woman for the Patient "to promote a useful marriage", and after Screwtape's receiving a painful punishment for having divulged to Wormwood God's genuine love for humanity (which Wormwood informed the Infernal authorities about), Screwtape notes that the Patient has fallen in love with a Christian girl and through her and her family a very Christian way of life. Toward the end of this letter, in his anger Screwtape becomes a large centipede, mimicking a similar transformation in Book X of Paradise Lost , wherein the demons are changed into snakes. Later in the correspondence, it is revealed that the young man may be placed in harm's way by his possibly Civil defense duties (it is stated in an earlier letter that he is eligible for military service, but it is never actually confirmed that he was indeed called up). While Wormwood is delighted at this and by the war in general, Screwtape admonishes Wormwood to keep the Patient safe, in hopes that they can compromise his faith over a long lifetime.
In the last letter, the Patient has been killed during a World War II air raid and has gone to Heaven, and for his ultimate failure Wormwood is doomed to suffer the consumption of his spiritual essence by the other demons, especially by Screwtape himself. Screwtape responds to Wormwood's final letter that he may expect as little assistance as Screwtape would expect from Wormwood were their situations reversed ("My love for you and your love for me are as alike as two peas ... The only difference is that I am the stronger."), mimicking the situation where Wormwood himself informed on his uncle to the Infernal Police for Infernal Heresy (making a religiously positive remark that would offend Satan).