"The intensity of the English game is so great that it makes it more difficult for those players to perform well in the World Cup," Ferguson told reporters at a news conference promoting Manchester United's four-game North American summer tour.
"You have to say the number of games, particularly at our level, is exhausting.
"Every game Manchester United play is a cup final. We have to win, and teams playing against us are motivated to play against Manchester United."
Ferguson said his players competing in the World Cup will be in urgent need of the 28 days of rest they are given before returning to training with United for next season.
"They must have that or they won't feature next year, they'll just collapse. Exhaustion will get them, which makes it difficult for English players to perform well in the World Cup," he added.
United's leading striker Wayne Rooney, who carries the weight of the nation's expectations every time he pulls on an England shirt, struggled with injury towards the end of the season but Ferguson said he would be fit for the finals.
"... if he wasn't (fit), there would probably be headlines all over the papers. I'm sure he'll be all right. I'm sure he's OK."
Asked who would win the tournament in South Africa which starts on June 11 Ferguson went with the form books. "My general view is that Brazil are very strong favourites with Spain following them," Ferguson told Reuters after embracing the head of United's U.S. supporters club following the news conference.
"...I think that France will do better than people think. They are underdogs, which is not normal for them, and Italy will probably get to the semi-finals."
