The Sign of Four was Conan Doyle's second attempt at rewriting Wilkie Collins's landmark detective novel The Moonstone. His first, published between A Study in Scarlet and The Sign of Four, was The Mystery of Cloomber (1888), a short novel that Doyle later came to regard as mere apprentice work. It is certainly derivative: its setting in a coastal village in south-west Scotland is strongly redolent of Stevenson, with an atmosphere recalling that of some of Doyle's favourites, such as ‘The Pavilion on the Links’ (1880). Technically, though, it follows Collins in its use of multiple narrators presenting their testimony, some of which takes the form of legalised witness statements and other official documents. But the influence of Collins is even more apparent in The Mystery of Cloomber's characters, plot and orientalist tropes. Like The Moonstone, it features a fugitive soldier haunted by a dark secret from his days of Indian service, a trio of mysterious Indians determined to fulfil a sacred trust, and a climactic scene at a sinister and remote watery location. All of these elements appear again in one form or another in The Sign of Four, albeit with the Indian trio becoming warlike and pragmatic Sikhs rather than mystical Hindus or Buddhists, and acquiring an Englishman to become a multiracial quartet. Furthermore, The Sign of Four adds further elements drawn from The Moonstone, including a wronged heiress, a cursed treasure and a killer gaining access to the victim via a trapdoor in the roof.

In terms of literary history, the most significant common factor in the three novels is their imperialist contexts, specifically Britain's wars in India. The primal scene of The Moonstone takes place during the Siege of Seringapatam at the end of the Fourth Anglo- Mysore War (1798–9): the siege provides an opportunity for the wicked Colonel John Herncastle to commit murder and then make offwith an enormous diamond which, unbeknownst to him, has great mystical significance. The genesis of the curse in The Mystery of Cloomber is a great imperial defeat: Britain's disastrous experiences in Afghanistan, now dubbed the First Anglo-Afghan War (1839–42), during which Doyle's brutal General Heatherstone kills a Buddhist priest trying to stop the vengeful slaughter of a troop of defeated Afridis.