Holders Porto will face Premier League leaders Manchester City while former European champions Ajax Amsterdam will meet Manchester United in two glittering Europa League Round-of-32 ties following Friday's draw.
All four teams were in the Champions League and dropped down to the Europa League and were, oddly, the first four teams out of the bag when the draw was made at UEFA's headquarters.
Davor Suker, who was making the draw, was unable to open the plastic ball containing Manchester City's name and in a moment of farce UEFA's director of competitions Giorgio Marchetti and general secretary Gianni Infantino had to help to twist open the ball and reveal Porto's opponents.
The two Manchester clubs, who are first and second in the Premier League and will play each other in the third round of the FA Cup next month, avoided each other in the Round-of-32 draw though they could meet later in a competition neither really wanted to be in.
City failed to qualify for the last 16 of the Champions League after finishing third in Group A behind Napoli and Bayern Munich while United, who have reached three of the last four Champions League finals, failed to advance, finishing behind Basel and Benfica.
The draw for the Round of 16 means the winner of the Porto-Manchester City tie will play either Porto's Portuguese rivals Sporting or Legia Warsaw. Whoever wins the Ajax-Manchester United tie will face Lokomotiv Moscow or Athletic Bilbao.
Braga, who lost last season's all-Portuguese final to Porto in Dublin, will face Besiktas in the Round of 32 with the winners meeting either Lazio or Atletico Madrid in the last 16.
The Round of 32 will be played over two legs on February 16 and 23 next year, with the Round of 16 on March 8 and 15. The final will be in Bucharest on May 9.