The main advantage of a 64-bit system is that it allows applications in 64-bit mode, which, in turn, is primarily useful if you need to access more than 4GB memory. If you have that requirement, using a 64-bit system is your only choice. Your application would be using 64-bit code, so WOW64 would not be used, and thus not cause problems.
If you don't really have the requirement to use more than 4GB of memory in a single process, it becomes debatable whether 64-bit Windows is really an improvement. You might need 64-bit Windows if you want to use more than 4GB of main memory at all (although you can also use PAE for that, which has its own disadvantages). Still, on a 64-bit system, you can run 64-bit applications. With AMD64 processors, 64-bit mode might be faster than native 32-bit mode, because the processor has more registers. Whether this slight gain outweighs the slight loss wrt. WOW64 depends on your application mix.
Personally, I think many people install 64-bit Windows because they don't fully understand the consequences of doing so, but feel they are on the safe side (which they may not, due to the lack of drivers).