Yup, so long as you only have one layout tab per dwg file. (NOTE, you can, actually, but you can't plot any extra ones via the publish commands that are available through the Project Manager.)
I normally use 11x17 landscape, with ladders, but when I have to draw pneumatics they go on 34x22 landscape, with grid references. They don't even plot out at the same device. The title blocks don't even look alike, graphically. I never have any problems; title block update works as it should, as do the 'Plot Project' and 'Publish to PDF' commands.
Hope this helps,
Jim
*EDIT* Just in case you do everything from model space, I'm pretty sure that the same thing applies: only one title block per dwg. While I do have some drawings that contain multiple layouts, they are each affected by the title block update command collectively. So I have to be careful about editing attributes in one but not the other. I'm not sure how this works if you have two title blocks in model space. I want to say that both would be updated, but who knows.
My instinct is to say you could have both your portrait and landscape title blocks exist in model space simultaneously, so long as they had the exact same values in all of the attribute definitions. They *should* both update when running that command.

Jim Seefeldt
Electrical Engineering Technician