Manchester United will look to eliminate AC Milan for the first time while Real Madrid seek a maiden victory over Olympique Lyon when the Champions League returns on Tuesday after its winter break.
In a move designed to allow more fans to see the matches on television, the round of 16 will be played on eight different evenings spread over a month featuring two games a night, rather than four evenings with four matches a night.
UEFA spokesman Rob Faulkner said: "The change means more fans have the chance to see the bigger games on television.
"UEFA will not earn any extra TV revenue as the number of matches remains the same."
The first knockout round will take from February 16 until March 17 to complete, with the return legs of Tuesday's matches not being played until March 10.
The two other ties kicking off this week are between Porto and Arsenal and Bayern Munich and Fiorentina, with the return legs on March 9.
The first leg of the eagerly-awaited clash between Jose Mourinho's Inter Milan and his former club Chelsea is not until February 24 when CSKA Moscow also play Sevilla.
Holders Barcelona return to action when they visit VfB Stuttgart on February 23 while Olympiakos Piraeus meet Girondins Bordeaux the same night.
While the game between Inter and Chelsea offers intriguing possibilites in a Serie A-Premier League clash at the San Siro next week, the stadium will host another Italy v England clash this Tuesday when Milan meet United.
United will be looking to knock Milan out of Europe for the first time after four straight failures since their first meeting in 1958 - three of those defeats coming in the semi-finals of the European Cup or Champions League.
Milan have won all four matches between the clubs at home and one of their players is especially looking forward to extending that run.
Former United idol David Beckham told reporters he had never before had to face the dilemma of separating his work responsibilities from his personal feelings.
"I've never had to do it before like this but I don't think it will be a problem. This is not just about me playing against United, it's about Milan qualifying for the next round of the Champions League - that's the most important thing," he said.
Another United old boy, Real Madrid winger Cristiano Ronaldo, will be hoping to face the Old Trafford team in a later round or even in the final in Madrid on May 22.
Real are looking for a first win over Lyon after losing on the two occasions the clubs have met in France and drawing twice at home, although the Spanish giants are unbeaten away in this season's Champions League.
This year's competition has a special edge for nine-times European champions Real as the May final is at their own Santiago Bernabeu stadium.
Lyon are back up to fourth after a poor first half of the season in Ligue 1 but coach Claude Puel says they need to do better - especially on Tuesday.
"We are not playing brilliant football but we have improved," Puel said. "We need to be more competitive, above all against Madrid."
Wednesday's matches see Porto face Arsenal while Bayern take on Fiorentina with the German side going into the home match having won their last 12 games in all competitions.
Bayern will be favourites to extend that run to 13 in temperatures likely to be as low as minus nine degrees Celsius.comments