Roberto Mancini, who is battling to claw back Manchester United's seven-point lead over Manchester City as he tries to retain the title, now has to overcome the loss of Yaya Touré for up to six weeks due to Africa Cup of Nations (CAN) duty.
Touré, plus his brother Kolo and Abdul Razak, a squad player, are all now missing from Mancini's plans as they leave for a meeting with the Ivory Coast that was a surprise as the Italian manager thought they would depart after Saturday's FA Cup third-round visit of Watford.
Perhaps significantly for the destination of this season's championship, United are one of only five clubs who will have no players absent when the remainder leave for the tournament, an exodus expected to start following the weekend's FA Cup action.
If the participation of Tottenham Hotspur's Emmanuel Adebyor for Togo is confirmed then a total of 18 players will take part in Can, of which City's three-man contingent is the largest.
Alongside the Touré brothers, Newcastle United's Cheick Tioté (also Ivory Coast), and Chelsea's Mikel John Obi and Victor Moses (Nigeria) are the headline names who could be missing from club action until after 10 February, should their nations reach the final in Johannesburg that day.
Of the absence of Yaya Touré, a pivotal member of Mancini's side, City's captain Vincent Kompany said: "He has played every game – that shows you how important he is for the team but that is something we will have to deal with. It is like having an injury, it happens. We believe we have enough players to step up and make the difference."
For Mancini, there is frustration that Sabri Lamouchi, the Ivory Coast head coach, insisted on taking the trio before Saturday. "We tried to keep them," Mancini said. "We spoke with the manager and he said they can't stay for this game – for three hours. It's just a meeting."
André Villas-Boas led Spurs to four wins in their last five matches and Adebayor is key to their 4-4-2 system, with the striker operating alongside Jermain Defoe. "It's a vulnerable situation, anything can happen," Villas-Boas said. "It was always his choice, I'm not going to put pressure on him. We've left it to the player. If player wants to go, we respect the Africa Cup of Nations."
While Adebayor decides, Newcastle's Shola Ameobi employed an unconventional method to avoid playing for Nigeria at the finals. After Alan Pardew continually insisted the striker would not be playing at Can, to which Stephen Keshi, the coach, responded Fifa action would be demanded if he did not, Ameobi decided to ignore his mobile phone.
"Shola's refusal to answer calls gave Keshi no other option than to allow him to concentrate on his club," Nigeria's media officer, Ben Alaiya, told BBC Sport. "The coach and team secretary made several attempts to reach Shola but there was no answer. The coach waited to hear back from him but a call never came. A decision on the next move will be made at the appropriate time."
At least, Millwall's Danny Shittu made clear his intentions to the Nigerian Football Federation, by writing to inform them he did not want to take part. After this request was turned down by the NFF, Keshi himself granted the defender's wish.