First-half goals from Leroy Lita and Kevin Doyle stretched Reading's lead at the top of the table to 13 points and left the Royals with a massive 24-point cushion between them and their nearest rivals for automatic promotion.
Beleaguered Southampton handed debuts to the trio of players they signed earlier in the week.
Striker Grzegorz Rasiak, winger Jermaine Wright and midfielder Richard Chaplow were all thrown into a Saints team looking to end an alarming slump that has left them hovering just seven points above the relegation zone.
Such is the gulf between these sides in fact, that Saints came into the game mathematically unable to catch the Royals, who look certain to be playing Premiership football next season.
Southampton were in that position only a season ago, but that looks a million miles away on this evidence.
George Burley has already conceded his side are in a relegation scrap and has signed seven new players since the opening of the January transfer window in a bid to rebuild his squad.
Steve Coppell has no such worries. In fact, the only headache for the Reading manager this time was who to pair up front, with top scorer Dave Kitson fit again after a hamstring strain.
Coppell, though, opted for in-form strikers Lita and Doyle and the decision paid handsome rewards as Reading swept into a two-goal lead before half-time.
Lita opened the scoring after 16 minutes, netting his seventh goal in his last six games for the runaway Championship leaders.
Doyle's searching pass into the penalty area looked easy pickings for Lloyd Dyer, but his hesitation allowed Glen Little to steal in and roll a low cross for Lita to fire in from close range.
And the ultimate destiny of the game was decided in a two-minute spell towards the end of the first half, with Saints wasting chances to level before Reading doubled their lead.
Rasiak spurned a glorious chance when he spun away from Ivar Ingimarsson but screwed a left-foot shot wide of the far post.
Seconds later, Reading had penalty appeals waved away as full-back Alexander Ostlund appeared to handle Bobby Convey's cross-shot and the Swede then raced to the other end of the pitch and headed Rasiak's cross against a post.
Those misses were quickly punished as Reading took the direct route to score a second.
Marcus Hahnemann's long punt forward was superbly controlled by Doyle, who then spun on the edge of the area and fired a low left-foot shot inside Bartosz Bialkowski's near post.
That ensured a mundane feel to the rest of the match, with Southampton rarely threatening a fightback.
Darren Potter fired a free-kick over the bar from an inviting position and Ostlund blazed wildly over after cutting in menacingly from the left late on.
But the game ended with Reading fans chanting "we are unbeatable", a claim that is beginning to appear accurate.