"Based upon the questions from the bench, I am predicting that there's likely to be a 5-4 ruling in this case. I tend to think it's a 5-4 ruling holding that the individual mandate is unconstitutional," said Lee on Fox Business Tuesday.
The high court is in its second of three days day of oral arguments to determine the legality of the healthcare reform law, which was passed in 2010 and has since been challenged in the lower courts by numerous state governments.
The Utah senator said that he was basing his conclusions on Supreme Court Justice Anthony Kennedy's questions, body language and reactions from the bench Tuesday.
Lee said that he sensed Kennedy, who is considered the traditional swing vote on the court, appeared "very skeptical" about the Justice Department's argument in defense of the mandate.
Most Republican lawmakers leaving the Supreme Court on Tuesday agreed with Lee's assessment, and predicted that the government will have a tough time finding a fifth justice to uphold the law's individual mandate.
Lee, who clerked for Supreme Court Justice Samuel Alito on the U.S. Court of Appeals for the Third Circuit Court, also noted that today's hearing was uncharacteristically "lively."
"First two-hour argument in one case in one sitting and very active questioning from the bench," Lee said.