The late 1800s were, in some ways, a more innocent time than today. Arthur Conan Doyle could publish stories of two chaps living together, one of them notoriously with little regard for women, without the slightest suggestion that the two might have been more than friends.
Watson certainly did have an eye for the ladies, and in about 1888 married Mary Morstan, heroine of The Sign of Four. There is some speculation that he may have been married previously, but that seems to be based on one specific chronology of the published stories, which may or may not be accurate.
But his marriage to Mary is unquestionable; and tragic: she died within a few years, during the time when Holmes was missing, presumed dead, after having fallen off the Reichenbach Falls in his death struggle with Moriarty. After Holmes astonishes Watson by his return in The Empty House, Watson notes “in some manner he had learned of my own sad bereavement”.
During his seven-year absence, Holmes wandered the world, studying may things, including Eastern martial arts, and certain sciences of poisons. It was the latter subject that raised a suspicion in my mind.
At the time of Watson’s marriage to Mary, Holmes accepted it with less than good grace. “I really cannot congratulate you” and “the only selfish action that I can recall in our association”. Quite camply jealous, in fact. And there were other occasions when the feelings that Holmes had for Watson look more like love than comradeship, such as the time when he was afraid that Watson had been seriously wounded in The Adventure of the Three Garridebs.
Well, enough beating about the bush. I think that Holmes returned secretly to England some time after his escape from death at the Reichenbach Falls, and poisoned Mary Watson, his rival in love. Even though her husband was an experienced doctor, he was duped by the symptoms caused by the secret poison recipe, and always believed that her death was from natural causes. It was the perfect crime.