And as The Early Show Correspondent Melinda Murphy explains, it didn't take long for him to get a big laugh with a his unusual "Top 10" list.
"There's nothing good about the BEEP shingles. The BEEP are so BEEP painful, every minute you pray some giant son-of-a-BEEP will shove a red-hot poker up your ass."
Yes. David Letterman is back.
"Welcome to the program. My name is Dave and I am back from my annual bypass," he said when he returned to the show. Only this time, it wasn't a bypass, but a case of shingles that affected his eyes.
"I looked like Nick Nolte's mug shot," joked the Late Show host.
The bypass reference is to the year 2000 when Letterman underwent heart surgery and was out for 34 days.
"After what I have been through, I am just happy to be wearing clothes that open in the front," he said when he returned on Feb. 21 of 2000.
Ironically it's the same number of days he's been out this time.
"You know you're spending too much time at the house when Dr. Phil starts making sense," he joked Monday night onstage at the Ed Sullivan Theater in New York.
And as he did last time, Letterman thanked his doctor and introduced the audience to his dermatologist.
He also paid tribute to the 14 guest hosts with a video medley to the tune of "That's What Friends Are For."
Viewers and critics admitted the guests were all talented folks, but let's face it, they're just not Dave.
"I began to miss Dave when the war started,," said media critic Adam Buckman, "and so I guess there is a correlation between a big story like that and having a stabilizing entity like David Letterman on TV. We missed him."
Meanwhile, Letterman joked about his illness: "You know how they got rid of this? Duct tape."
"I think David Letterman, more than Jay Leno, has a knack for realizing that a war in and of itself is a tragic event," says Buckman of the New York Post.
"And I don't think he's going to use it as fodder for jokes the same way that Jay Leno has."
For example, Leno recently joked: "Well, today President Bush said we'll stay in Iraq for as long as it takes. The same policy he had in high school.... we'll stay there."
But of course, Letterman has a track record of knowing just how to handle difficult times, as he did in his critically acclaimed show after Sept. 11.
He said on Sept. 18, 2001, "We're told that they [the hijackers] were zealots fueled by religious fervor - religious fervor - and if you live to be a thousand years old, will that make sense to you?"
Colin Quinn of Comedy Central said, "You can tell after Sept. 11, it moved him. So yeah, you look to a guy like him for his particular brand. So he doesn't pretend that it doesn't affect him and it's kind of good, you know, and he still happens to manage to make humor out of it."
Quinn has one of the most edgy topical shows on television, Comedy Central's "Tough Crowd."
"War is a sensitive subject. Is it OK for us to do jokes about the war? We're all comedians. Yes?" he asked his audience on Tough Crowd.
But even Quinn is careful to keep it respectful.
"If it's done correctly, it's a stress reliever and you can talk about things that other people can't talk about," Quinn said.
And perhaps nobody does that better than David Letterman.
"Thirty days it took me to get over the shingles," Letterman joked. "And according to Donald Rumsfeld, that's right on schedule
Of course you can see Letterman back in his regular time slot on CBS.