The first of the seven remaining home fixtures this season sees Saints take on second placed City, who sit seven points clear of the teams below them, but trail rivals Manchester United by nine points at the top of the table going into the weekend.
However, their manager Roberto Mancini refuses to believe that time is already running out to stop City’s rivals Manchester United from snatching the title back off them.
“This championship is not over, absolutely not,” says the City boss. “There is still time for a team to make a mistake.
"We probably now need to win all of our 13 games, but if not 11 or 12."
With an admission of little room for error from the opponents, Saints will be keen to pile the pressure on to a City side who they ran so close with on the opening day of the season, when the champions had to fight back from 2-1 down to take a 3-2 win at the Etihad Stadium.
Goals from Rickie Lambert and Steven Davis saw Southampton dare to dream on that day, but their opponents battled back to take all three points.
That was a familiar story as recently as last week for Saints when Manchester United overturned a deficit on Mauricio Pochettino’s side to win at Old Trafford, before Saturday’s trip to Wigan saw Saints denied a win late on in a 2-2 draw at the DW Stadium.
Pochettino will be hoping that Southampton’s encouraging performances from his opening three matches in charge continue this weekend, and will look to build on a run of just one defeat in the last eight league matches.
A number of Saints stars have been representing their nations this week, but three of those due to be away, Nathaniel Clyne, Luke Shaw, and Gaston Ramirez, were all withdrawn after picking up knocks. All three will be assessed prior to the weekend’s game.
José Fonte and Guly remain out, but striker Emmanuel Mayuka has returned from African Cup of Nations duty, and could be welcomed back into the squad.
City also have players back from Africa, with Yaya and Kolo Toure almost certain to be involved.
Captain Vincent Kompany is also hoping to recover from a calf injury in time, but long term absentee Micah Richards will not be available for selection.
Saints haven’t beaten City in their last six attempts, with the last meeting at St Mary’s ending in a goalless draw during the 2004-05 campaign.
The last three competitive matches between the two teams have taken place at the Etihad Stadium with City winning all of them, including an FA Cup meeting in 2007.
The last meeting was at the start of the current season, a game which marked Southampton’s first game back in the Premier League for seven years.
Kelvin Davis saved a 16th minute penalty from David Silva, but Saints trailed to a Carlos Tevez strike going into half time. Rickie Lambert came off the bench to level the scores shortly after coming on as a substitute, before Steven Davis gave Saints a 2-1 lead. Late strikes from Edin Dzeko and Samir Nasri earned the hosts a 3-2 win.
Martin Atkinson will referee Saturday’s game, and he will be assisted by Mr S Burt and Mr P Kirkup. Lee Mason is the fourth official.
Tickets are sold out for this game, but limited hospitality spaces do remain, contact 0845 688 9377 between 8.30am and 6.30pm or email firstname.lastname@example.org
The match is being screened live on ESPN with kick-off at 5.30pm.
As with every First Team game, we'll be providing minute-by-minute coverage throughout the day on our official Twitter
feed plus goal updates on our official Facebook
You can listen to live commentary courtesy of BBC Solent on Saints Player
, where you can keep up to date with all the stats and scores from around the country.
Members of the first team and manager Mauricio Pochettino will be speaking to Saints Player
ahead of the game, and you can watch his interview on the club’s official video channel later this week.