How much does it matter(or not matter) to you when a voice actor behind a significant character gets replaced?

To me, it's fairly important. Michael Ironside is Sam Fisher, Nolan North is Nathan Drake,(and many other characters) David Hayter is Solid Snake, and so on IMO.

I'll probably never get around to playing Splinter Cell: Blacklist because of the absence of Ironside, well that and because SC seems to have jumped the shark.

Very important. Simon Templeman will always be Kain. David Hayter will always be Solid Snake. But there is a severe lack of Patrick Stewart though. Could of used more of him in Oblivion.

If they're high profile or synonyms with a role it can be tricky and I'm not sure how I feel about David Hayter not voicing big boss but then again he didn't voice big boss in mgs 4 so

But if Ron Pearlman didn't do the war, war never changes... quote in the next Fallout (like rumors have suggested) I'd struggle to accept that.

Harry Robin is Issac Kleiner

Merle Dandridge is Alyx

Michelle Forbes is Judith Mossman

and Robert Guillaume is Eli Vance

This is because I've played the games so many times that if it isn't the same people it wouldn't feel like the same characters.

Depends on who it is. Sometimes, the actor and the character become one, and when they get replaced, it's just not the same. Ironside and Hayter have always been Fisher and Snake, it's just not the SAAAAAAAAAAM E!

It varies from game to game, but it did annoy me greatly when Square-Enix decided to use different voice actors for 47 and Garret (fortunately with 47 they switched back to the old one after a fanbase outcry).

It depends... I mean in the Legend of Spyro trilogy, Sparx had a different voice actor every game but every actor played the role pretty good. (You know, comedy sidekick type of role). Heck, they even made a joke in the 3rd game where Sparx mentions "Oh, I'm doing good... Voice changing and such."

But if they change the actor of a very specific and major character, it could really ruin the character and even the game for me...

Actually, Big Boss/Naked Snake was voiced by Richard Doyle in MGS4, and Hayter's voice was getting worse each game, so I really dont mind Kiefer replacing him.