Being one of the most popular literary characters of all time, the Master Detective has come across many opponents in his illustrius career. Be they creations of his creator Sir Arthur Conan Doyle, or "non-canon" crossovers with other characters from across the world of literature.
Can't start a list without including THE MOST POPULAR OPPONENT. Despite only appearing in BARELY two of the original Sherlock stories, it was the fact that he not only severely taxed Holmes' abilities, but almost bested the Detective, that has led to his immense popularity. The "Napoleon of Crime" has since appeared in various novels/pastiches/movies/games/comics in subsequent rematches.
Moriarty's right-hand man, this former military-man (and thug) is also a popular mainstay in the Holmesian universe. Appearing either alone or with his boss.
while technically not a "villain", she still matched wits with Sherlock, and even outsmarted him. His seeming admiration for such a feat (dubbing her "THE Woman") has led to many subsequent encounters outside the original series.
If there's one fellow, besides Moriarty, that Holmes has faced off against the most... it is (without a doubt) Jack the Ripper. It makes sense, the world's greatest detective facing off against the world's most legendary serial killer case. Novels, Movies, Comics, TV shows, and even a game or two.
It was bound to happen, and ironically it was Lupin's creator that kick-started it all (much to Sir Arthur Conan Doyle's displeasure). The Master Thief has faced off against Holmes (or one of the many various analogues LeBlanc had to create) on more than one occasion.
Now we're getting into the more paranormal/supernatural side of things. King of the Vampires vs. King of the Detectives, it's been done quite a few times over the years. Most recent example being the sequel to "Victorian Undead".
The Phantom has proven to be a favorite amongst some authors/comic writers at times. Usually with Sherlock being inserted into the original story's setting somehow.
Not exactly Cthulhu himself, but more along the lines of Holmes finding himself knee-deep in the Lovecraftian Mythos itself. Biggest example being the game "The Awakened" by Frogware games.
Holmes has had more than one run-in with this victim of science and split personalities. Most recent being a "midquel" set between Victorian Undead I & II
The master criminal genius has crossed paths with Holmes on at least three occasions ("Ten Years Beyond Baker Street", "The Musgrave Version" and "Elemental, querido Chaplin").
The legendary French villain has had at least TWO encounters with Sherlock Holmes ("Sherlock Holmes vs. Fantomas" and "The Grand Horizontals").
Sherlock ran into this unseen maniac on at least one occasion, the story "A Case of Blind Fear" by Eternity Comics.
