O'Connell was able to partake fully in training from the start of this week. It looked as though he had put his back injury behind him.
Sadly, he suffered a reaction to the sessions. He will see a specialist in the near future and an update will be issued in due course.
Coach Declan Kidney will offer a glimpse into the future when he names the new captain.
With seasoned campaigners O'Connell, Brian O'Driscoll, Sean O'Brien, Stephen Ferris, Rob Kearney and Rory Best missing, Kidney is having to delve deep into his playing resources.
The optimistic prognosis over O'Connell's back injury was confounded yesterday when the 2009 Lions skipper's recovery was hit by a complication, forcing him out of the Springbok test.
"Paul returned to training at the start of this week and took a full part in the squad sessions on Monday and Tuesday," read a statement released by the Irish Rugby Football Union.
"However, he suffered a reaction and will not be fit for selection for this weekend's game.
"Paul will see a specialist in the coming days and an update will be issued in due course."
Ireland have lost their last four tests, the most recent of which was their 60-0 mauling by New Zealand in June.
With IRB ranking points critical to seeding for the next World Cup at stake, it is imperative they dispatch opposition that is also missing several big names.
South Africa remain heavy favourites for Saturday's match.