The only woman to impress Holmes was Irene Adler, a character introduced in A Scandal in Bohemia who, according to Watson, was always referred to by Holmes as "the woman". Holmes himself is never directly quoted as using this term and even mentions her name in other cases (although it is worth noting that all of the stories using Adler's name come after A Scandal in Bohemia, which was the third tale published about Holmes and the first short story so Holmes may have shifted how he referred to Adler over time). Adler is one of the few women who are mentioned in multiple Holmes stories, appearing in person in only one.

In one story, The Adventure of Charles Augustus Milverton, Holmes is engaged to be married, but only to gain information for his case. Although Holmes appears to show initial interest in some of his female clients (in particular, Violet Hunter in The Adventure of the Copper Beeches), Watson says he inevitably "manifested no further interest in the client when once she had ceased to be the centre of one of his problems".

Holmes states: “I have never loved, Watson, but if I did and if the woman I loved had met such an end, I might act as our lawless lion-hunter had done”. In the story, the explorer Dr Sterndale had killed the man who murdered his beloved, Brenda Tregennis, to exact a revenge which the law could not provide. Watson writes in The Adventure of the Dying Detective that Mrs. Hudson is fond of Holmes in her own way, despite his bothersome eccentricities as a lodger, owing to his "remarkable gentleness and courtesy in his dealings with women". Again in The Sign of the Four, Watson quotes Holmes as saying, “I would not tell them too much. Women are never to be entirely trusted.not the best of them”. Watson notes that while he dislikes and distrusts them, he is nonetheless a "chivalrous opponent".