ED: It occurs to me that you said 'ONE' in all caps, like it was important and everything. 

Without a doubt, All-Star Superman by Grant Morrison. 

For the long winded Karl Van-Hœt, continue below. 

Hoo Boy. 

First off, Two (Two!) shameless plugs: the Episode I did with 5by5's own Comic Shack  and, my Non-Superhero Comic Review site, Spandexless. Lots of 'First comic' gold in both of those.

Now on to the recommendations. I would consider any of the following a great pick for a first-time comic reader. Take your pick from what interests you: 

As a DC fan: 

- Wonder Woman Volume 1 (Single Favorite book DC puts out right now, and I am not even a huge WW fan. Just amazing.) 

- All-Star Superman (Single Greatest Superman story ever told. Yes, I know. Superman is superman - unapproachable and distinctly alien. I can not stress how good this is.) 

-Animal Man Volume 1 (Great grotesque art, and it plays well with...) 

- Swamp Thing Volume 1 ( Another great looking read.) 

- Action Comics Volume 1 (A much more approachable young superman.) 

- Batman Voume 1 (The Dark knight at his finest.) 

The above (save for 'All-Star Superman', which is a few years old) are the absolute cream-of-the-crop of the New 52. There are a few other serious standouts, but the ones above really take the cake. 

For Non-Capes stuff:

- Daytripper (I bust a gut in the Comic Shack episode, but this comic makes me bawl, and I don't even have a kid. Merlin, I would be very interested to hear your reaction to this.)

- Skullkickers (Great fun, rollicking action title.)

- Any Volume of American Splendor (Just Read It.)

- Transmetropolitan (Hunter S. Thompson meets the future. Mm-mm.)

- Habibi (The single most gorgeous comic I have ever seen.)

There'll be something for everyone in there.  

I'll go with One Piece, for the reasons I outlined in probably the best thing I ever wrote.

I just finished the Astonishing X-Men and I loved everything about it. I did feel like there was some in-jokes going on that I did not get because I had not read X-Men before, but then Wolverine needed a beer and everything was O.K. :)

I'm not a huge comics reader, but The Alchemy, the seventh book in David Mack's Kabuki series, is one of the coolest things I've ever had the pleasure of owning. It hops artistic media from ink to watercolor to acrylic to decoupage to origami to pencil sketches on graph paper, and all in a way that is fluid, coherent, and positively beautiful. The story is entertaining and thought-provoking, exploring the nature of art, productivity, distruption, and the role of the artist in the world. And, for the nerds, it's positively filled with strange loops. Cannot recommend enough.

Did anybody say Sandman yet?

Somebody really should. If only for Delrium. 

And the potential for an "All Things D" pun.

I'm a Marvel fan though and though, just couldn't get into DC. Marvel to me was more gritty and human. One I recommend is the Infinity Guantlet series. That was my first Marvel mash up and had a really great villian.

Also seeing Cap and Thanos face to face was great.

As Sandman has already been mentioned I suggest either

Watchmen (for the super hero stuff) or

From Hell (for the rest)

by Alan Moore. And read them even if you didn't like the movies. 

WE3 by Grant Morisson. It's...it's just awesome. It's about a cybernetic dog, cat, and bunny rabbit, but awesome.

I came back to comics this past summer after not reading them for probably 15 years. Wow. Lots of catching up to do.