Rescuers battled to revive the former player, who turned 88 , after his heart and breathing stopped while he was in central Madrid, said a source at Madrid Emergency Services.
"He had suffered a cardiorespiratory arrest. The emergency services began resuscitation and after 18 minutes managed to get him out of the arrest and he nwas taken in a serious condition to the Gregorio Maranon hospital," the source told AFP.
The Argentinian-Spaniard is now lying in a coma in the cardiac ward of the hospital, a hospital spokesman said.
"He suffered a heart attack and was taken to the cardiac unit of the Gregorio Maranon hospital," he told AFP.
"His status is that he is in a coma and we are keeping an eye on his progress."
Leading newspaper El Pais said Di Stefano had been eating with his family near the Santiago Bernabeu stadium when he felt ill and sat down on his wheelchair.
By the time an ambulance arrived he was in cardiorespiratory arrest.
According to the paper, Di Stefano had been hospitalised seven times for similar episodes, none of which were as serious as the latest attack.
Di Stefano is one of Real Madrid's most celebrated players, having represented the club for 11 seasons between 1953 and 1964, winning five European Cups. He now holds the title of honorary club president.