The Red Devils were linked with a move for De Marcos last season after their exit from the Europa League at the hands of Bilbao, and now appear set to rekindle their interest after sending scouts to run the rule over the 23-year-old.
Manchester United boss Sir Alex Ferguson sent brother Martin, his leading European scout, to watch De Marcos in action against Barcelona over the weekend.
A move for De Marcos would represent an attempt by Ferguson to add some fresh legs to his midfield, with both Paul Scholes and Ryan Giggs entering the twilight of their careers.
Bilbao have struggled badly this season having made the Europa League and Copa de Rey finals last time round and could be facing an exodus of their leading players.
Striker Fernando Llorente looks set to leave the San Mames Stadium amidst interest from their Premier League, while De Marcos and Iker Munian have attracted interest from around Europe. Key midfielder Javi Martinez joined Bayern Munich over the summer.