Boro have scored just 13 times in 14 games this season, with Negredo and Ramirez responsible for four of their last six goals.
But the pair have not been fit enough to take part in training ahead of the trip to St Mary’s and Negredo’s most likely stand-in up front, Rhodes, has also been sidelined.
Manager Aitor Karanka has not yet ruled anybody out but has been assessing the likes of Cristhian Stuani and David Nugent this week, should they be required against Saints.
“We have maybe a few injuries,” he said. “Jordan Rhodes couldn’t train, Gaston and Negredo couldn’t train with the team, so let’s see what happens.
“The main thing for me is the players who are ready to play because all of them are ready to take that chance.”
One man who will be eager to get the nod is winger Adama Traore.
The former Barcelona and Aston Villa man has started just five games this season but has caught the eye at times with his direct pace and power. Yet the 20-year-old was an unused substitute in Monday’s 1-0 win over Hull and Karanka offered no promises to him or any other player about their future role.
“We need to always try to put the best 11 on the pitch and that day I thought Adama wasn’t the best,” he said. “One thing that was good for me, good for the team, good for everybody was we won the game without Adama and were better than Hull.
“Nobody is untouchable. The player who is playing knows if he doesn’t perform well the following game he will be on the bench or in the stand because we have 26 who are ready to play.”
Karanka went on to suggest that his team were well on the way to disproving critics who have painted them as an overly defensive outfit.
Boro picked up draws away to Arsenal and Manchester City by defending in numbers and holding their shape but were more expansive in a 2-2 draw at Leicester and the subsequent win over Hull.
“After our good games against top teams, I had to hear we were a defensive team but when we played against Leicester and against Hull we showed we know how to play when we have the ball. We can play,” he said.
“It is not the same to play against Arsenal or Manchester City in their stadium as it is to play at home against teams like Hull.”