The reigning Associated Press Defensive Rookie of the Year was suspended in May for testing positive for HCG, a fertility drug that is on the NFL's banned substances list. Cushing claims that he has a unique medical condition that triggered the positive test.
"At the request of Texans owner Bob McNair, commissioner (Roger) Goodell reviewed additional medical information presented on behalf of Brian Cushing," the NFL said in a statement.
"The club and Cushing were notified today that after carefully considering all the information, including a review by outside medical experts, the commissioner finds no basis for changing the decision that Mr. Cushing's suspension for the first four games of the regular season remains in place."
Cushing will miss games against Indianapolis, Washington, Dallas and Oakland before becoming eligible to return Oct. 10, when Houston hosts the New York giants.
Cushing missed practice Thursday with a foot injury and was not available to comment.
The former first-round draft pick started every game at outside linebacker last season, making 133 tackles and helping solidify the Houston defense. The Texans went 9-7 and just missed the AFC playoffs, their first winning record in their eight-year franchise history.
Xavier Adibi, a third-year pro who started five games in 2008, has backed up Cushing during training camp. The Texans also might move starting weakside linebacker Zac Diles into his place.
"We move forward. One guy goes down, the next guy just steps in," fellow linebacker DeMeco Ryans said. "Expectations don't drop. We just keep pushing."
Cushing's suspension does not apply to the preseason. Houston plays defending Super Bowl champion New Orleans on Saturday at the Louisiana Superdome, after practicing with the Saints on Wednesday and Thursday in nearby Metaire, La.
Asked whether he expects Cushing to play, coach Gary Kubiak replied: "I sure hope so."