After missing two games with an undisclosed illness, Letang continues to not feel well and will undergo further evaluations. It is uncertain if Letang's ailment could be long-term, Penguins coach Dan Bylsma said.
The 2013 Norris Trophy finalist has missed 21 games entering Monday due to various injuries.
Pittsburgh is 16-5-0 without Letang this season, but defenseman Matt Niskanen said the Penguins will need to increase their quality of play if they are to compete with Ottawa after losing 3-1 against the Phoenix Coyotes on Saturday.
"They play hard, they have a good mix of skilled veterans and young energy guys that can skate," Niskanen said. "They play a fast game. [Craig] Anderson's a good goalie. Where they're at in the standings, they're going to bring it.
"They're a good test for us and a good thing for us to keep getting better at those tight-checking games, those tightly matched games."
The Senators defeated Pittsburgh 5-0 when Letang was out with an upper-body injury on Dec. 23. But Ottawa captain Jason Spezza said the Penguins are dangerous with or without Letang.
"Their power play is probably a little different missing him," Spezza said. "He's elite back there and he shoots it and sees the ice, but I think he's been out for a lot of games this year and they've had a lot of success anyway. They have some pretty creative guys over there.
"But you definitely pay attention to that stuff."
Here are the expected lineups for the Senators and Penguins: