I just finished the main quest line a few minutes ago and thought it might be interesting to others to know that, yes, the main quest can be completed without glitches.

I'll throw up my stats here but I should say that my character was never intended to consume all content. He was a warrior who basically ignored the Thieves, Mages and Dark Brotherhood quest lines. That being said I did finish the core Companions Quest line (still have some radiant quests to do I think) and the Main Quest Line.

Some Finishing Stats

Level: 52
Hours: 140
Save game File: 13mb
Locations Discovered: 231 (I plan to go back and find more)
Locations cleared: 119 (probably will do more)
Quests Completed: 67
Misc Objectives Completed: 247
Dragon Souls: 40
Words of power: 45
Shouts Learned: 20 (all of them, although some still need some of their words found)

Quest Issues

Panteas Flute Quest bugged - Found item before I got the quest
Hagraven Petra - Killed Petra before letting other Hagraven out of the cage (Quest Bugged)
Investigate the Bards College - Unsure what happen but can't advance or remove from log (could be related to Pantea bugged Quest)
Disrupt Skooma Operation - Cleared dungeon before I received the quest. (Bugged)

I could not get the houses in Riften or Windhelm. Riften because of the Skooma Quest and Windhelm becuase I can't get the murder quest to kick off.

Other Issues

Resistances post 1.2 patch - Seemed to be hit and miss for me. Sometimes they appeared they were working. Today I breezed through the final quests, the Dragons and High Level Duerger Scourges barely touched me, but other times I was getting spanked by forsworn mages.

Backwards Flying Dragons - Only one definite one that I saw. I ended up using the wait command for 1 hour and he started flying forward again but would not land so I just went to the wall, got the word and left.

Lockups - A handful. I would say 5 or 6 total in 140 hours of play

And then the biggie the Lag!

Most of my lag was pre-patch although I did see it sneak in post patch to a lesser extent. It was never much of an issue for me because it usually showed up after hours of playing. Restarting the game was all it took to resolve it. I used Autosaves throughout the whole game. I never turned them off.

Based on the most recent information about persistent references and such I wonder if my luck had anything to to with my deciding not to do everything with one character. My character also didn't leave a massive footprint on the world. My cities were not littered with NPC corpses from Dragon attacks. I sold most of my equipment and did not try to keep too much. I had my worst lag bouts in Whiterun where I did have the most stuff stored in the house and where, pre-patch, I had several dragon corpses laying around. I did not pickpocket or steal from any homes, which may have also helped lower the persistent references that changed in my game.

Then again maybe I just got lucky.

My Conclusion

Does the game have issues that need to be fixed? Absolutely!!! But, to declare the game completely unplayable is not accurate either. I am sure that for some it is unplayable or that major quests are broken but it is not everyone having those issues. Not everyone is lagging badly. Not everyone is locking up every five or ten minutes. This makes Bethesda's job that much harder. If everyone had the same exact problems then it would be far easier to pinpoint the problem and correct it. But when it is hit and miss then things get far more complicated to figure out the issues.

Bethesda, keep looking for solutions and patch as much as you need to in order to get this game stable for the biggest majority of the players. Be careful though as the 1.2 patch was far more detrimental than helpful to me. None of the issues in mentioned in the patch log were major issues for me but post patch I experienced problems that were introduced by the patch itself (resistances and backwards dragons)