I own both and yes, there is a big difference between the ER4 and ER6.
For comparisons sake, I am using the ER4s (unampped) I know they would sound their best with an amp, but I mainly use them to travel and with my ipod.
ER4 - The ER4 is a wonderful headphone. When I first heard them, my jaw did drop. They were wonderfully clear , detailed and a joy to listen to. With these cans, you will find yourself listening to your favorite CDs over and over again. The soundstage is incredible. I would best describe it as having a tiny orchestra in your head. You are easily able to pinpoint with utmost accuracy of where each and every instrument is placed. The bass is tight and the mids are very good. I have found that if I use with my META42, the sound can be a bit bright and too foward for my tastes. But just out of the ipod jack, it just 'feels right'
ER6 - I got many of the similiar sensations as with the ER4, but to me the sound was a *tiny* bit more muffled. They do sound great, and still have the same amazing ER4 sound sensation, but it is just a tad toned down. Not as critical sounding, but very clean nonetheless. The bass is very good as-is vocals. You may not have heard the Eggo D66, but the sound is very similiar, but a lot more refined and more clarity.
The ER6s are very_very good in their own right. I can't think of many cans under $100 that has the same impact and wonderful sounds that the ER6 can produce.
But to really answer your question. Yes, there is a big difference. You will notice them right away if you A/B them. But if you are not an audiophile or require to have the *BEST* you'll be more than satisfied with the ER6. A weird test I did was put one ER4 in one ear and the ER6 in the other ear. I used 2 different ipods playing the same song completely sync'd. Needless to say, it was quite a weird sensation, but I can clearly see where the ER4 is superior. It's just a lot more clear and better sounding all the way around. The highs extended a bit more.
Oh yes, I have found the ER6s to be much easier to seal than the ER4. With the ER6, I can pull them in / out quickly and get a qreat seal everytime. With the ER4, I need a few seconds of fidgeting to get them 'just right'
Both are very comfortable to use after your ears get used to them. Both are absolutely amazing. The first time you try them and really get a good fell for them, you will be absolutely stunned!