Bjorn Basson and Chiliboy Ralepelle will both be sent home from South Africa's squad after testing positive for a banned stimulant.
The pair were randomly tested after the Test match victory against Ireland in Dublin on November 6, and both have tested positive for banned substances.
Six Nations Rugby, who administer the November internationals, confirming to the South African Rugby Union that they had tested positive for methylhexaneamine.
Basson was already duo to leave the tour because of an ankle injury picked up against Wales on Saturday, but the two players will head for South Africa today under different circumstances.
Basson won his third cap in the 23-21 win against Ireland and is the record holder for the most tries in a Currie Cup campaign.
Ralepelle is slightly more experienced than Basson, having picked up 17 caps, while he was also the first black player to captain the national side when he led them out against a World XV in Leicester.
The 24-year-old hooker plays his club rugby for the Blue Bulls and came off the bench in Saturday's win over Wales.
Basson started the game against Ireland, while Ralepelle was an unused substitute.
A statement from South Africa Rugby Union confirmed the players had been provisionally suspended from all rugby but could request their 'B' samples be tested.
"Six Nations Rugby Ltd - who administers the November internationals - informed the South African Rugby Union of the positive Tests on Sunday evening," said the statement.
"As a result the pair are provisionally suspended from all rugby and will return to South Africa on Monday. Basson injured an ankle in Saturday's win over Wales and was due to return anyway.
"The players were randomly drawn for testing by anti-doping officials following the Test at the Aviva Stadium. The players have the right to request that their 'B' sample be tested.
"The pair returned an adverse analytical finding for methylhexaneamine, a "non-specified stimulant" on the prohibited substances list of the World Anti-Doping Agency (WADA). It is scheduled to be re-classified as a "specified stimulant" from 1 January 2011."
The pair were reportedly being treated for flu symptoms, sparking concern in the camp that more players could have inadvertantly taken the substance.
"If there is something that we are taking as a squad that might have caused this then we must find that out now," coach Peter de Villiers told supersport.com.
"When I informed the two players that they had been tested positive they were both extremely shocked and disappointed. The rest of the team were also gutted when they heard.
"I was informed of this at 2am this morning, and now we must follow the correct processes as laid down by the International Rugby Board."
Team doctor Craig Roberts shared De Villiers' desire to get to the root of the problem.
"The substance could come from many different sources, like the caffeine substances. What we are doing now is going through the process of looking at all the possibilities and exhausting them one by one. Obviously we need to get to the bottom of this as quickly as possible."