I should have stipulated that I get the above readings running at 24/96 with a buffer size of 256 samples. I just lowered the buffer to 128 (don't usually run it that low) and playback was smooth (12-track project) and the total round trip is 3.4 msec.
 
This is making me think I should just shut up and use what I have, and go to a commercial studio if I ever need to record with more inputs.

Larry, now that you have given your exact settings:
 
My UR44 running 24/96 with a buffer of 256 samples through Sonor Platinum 64 PC
 Edit:
Input: 3.1 msec 295 samples
Output: 3.5 msec. 338 samples
Total Roundtrip: 6.6 msec 633 samples
 
So I guess you beat me by a shade. I have a very fast PC so check my stats.
 
 

Rimshot - are you sure about that? That seems awfully low for 256 samples.

Larry - I don't think you're going to like going from 6 ms to 12 ms. I record guitar through amp sits like you, and get 5 - 6 ms rt latency at 64 samples with a PCI card (like you). At 128 samples, it's 7-8 ms but you can hear the lag, if you hear the actual electric guitar strings being hit (vs the amp sound coming through headphones).

I'm going to bite the bullet (I hate spending this much on a audio card) and get a MOTU Ultralite AVB or RME fireface UC. Jim Roseberry says they both go down to 4.8 ms at 64 samples.

Rimshot
Larry, now that you have given your exact settings:
 
My UR44 running 24/96 with a buffer of 256 samples through Sonar Platinum 64 PC
 Edit:
Input: 3.1 msec 295 samples
Output: 3.5 msec. 338 samples
Total Roundtrip: 6.6 msec 633 samples
 
So I guess you beat me by a shade. I have a very fast PC so check my stats.
 

Rimshot - That's close enough to what I'm used to that I know I could work with it. I wonder what buffer settings musichoo used to get his 12.8 msec round trip. Looks like the Focusrite driver is calibrated in time, not buffer size.

I run my UR44 at 64 samples recording at 24/48. All I do is small projects but it's a great unit with tons of features. I've yet to play with the ability to output 2 different headphone mixes, but I'm sure it will be useful. From what I can tell the 4 amp sims are based on the Yamaha DG series. The included reverb has everything I need and has become my go to.

I should also add that the phantom power is supplied to the 4 mic pre amps in pairs. You can have it on none or any 2 or all 4. 
 

ampfixer
I run my UR44 at 64 samples recording at 24/48. All I do is small projects but it's a great unit with tons of features. I've yet to play with the ability to output 2 different headphone mixes, but I'm sure it will be useful. From what I can tell the 4 amp sims are based on the Yamaha DG series. The included reverb has everything I need and has become my go to.

John - Are the amp sims built into the hardware, or are they VSTs that work only with the host? That is, can you use them as part of the "near-zero latency" monitoring setup, or only through your DAW?

I will have to check my setup again and report back. I know that at the mix control the setting is 44.1khz and 2 ms. 1ms is the smallest setting by my ivory ii piano won't play nice. Sound quality wise it is a huge big upgrade from ua25ex.

Just as an observation, we were using  S-Gear, Bias, and TH-2 as VSTs, and they work great at 2.9 ms on the 2i2. At 2 I get some dropouts with everything going. That includes a one track drum loop from EZD. Oh and 128 samples.
 
The new Win 10 beta driver cleans things up a bit. It has 3 choices, recording, balanced and mixing. Plus no more math for buffer size.

The EFX are VST's that can be applied to the real time monitoring and are also available thru your DAW.
You cannot apply these EFX to the signal going into the DAW - only after. 
However, it has been really nice to create a live setting with compression and reverb and play along with YouTube videos. It can sound great with electrical or acoustic guitars. You can then save the custom setup as a program to recall anytime. 
 
I have tested the 2nd monitor mix with Studio One and it works great. In Studio One, the mixer will show the "Cue Mix" where you can adjust pan and level just for that output.