I run LOTRO on mulitple clients with Inner Space on Vista 64.

A couple of notes:

A) Can't use DirectX10 in LOTRO. Make sure to disable it (it's in the Graphics options)

B) The default profile that Inner Space sets up for LOTRO sets it up pretty spot-on to be able to send keystrokes to those instances in the background

C) For multiple clients on a single computer, make sure to set ComputeUniquePort=false (Thanks Lax!)

D) Lax is generally on his IRC server for support whenever I've needed help.