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Real opened up a four-point advantage over nearest rivals Barcelona at the top of La Liga by beating Sevilla on Wednesday, with Rodriguez opening the scoring in the 12th minute.
However, the Colombia forward was forced from the field 15 minutes after finding the net with a diving header and coach Carlo Ancelotti revealed in his post-match interview Rodriguez will miss Saturday's derby against Atletico Madrid.
A subsequent update on Real's official website confirmed the 23-year-old requires an operation.
It read: "Following tests on James Rodriguez for the medical services of Real Madrid in the Hospital Sanitas La Moraleja, he was diagnosed with a fracture of the fifth metatarsal of his right foot.
"The player will undergo surgery in the coming hours."
