Nigel Pearson's reign as Southampton boss got off to a disappointing start as first-half goals from Peter Halmosi and James Paterson gave Plymouth a convincing 2-0 win in the Coca-Cola Championship at St Mary's.
Despite starting brightly, Saints went behind after 31 minutes when Lilian Nalis played in Halmosi, who clipped the ball past Kelvin Davis.
Things went from bad to worse two minutes later when Paterson curled home an excellent long-range effort for his first Plymouth goal since joining the club from Motherwell.
Pearson made three changes to the side beaten by Bristol Rovers in the FA Cup, with Wayne Thomas coming in at the back for the injured Alex Ostlund, while Gregory Vignal and Bradley Wright-Phillips replaced Jhon Viafara and Inigo Idiakez.
On-loan defender Russell Anderson made his Plymouth debut a matter of hours after his move from Sunderland, while fellow new boy Gary Teale had to make do with a place on the bench.
Southampton started well and Vignal's deep cross from the left found Marek Saganowski at the far post, but he volleyed well wide.
The visitors came back and Andrew Davies did well to block Jermaine Easter's cross-cum-shot before the Saints defender headed wide at the other end.
Thomas also nodded over as Southampton continued to press for the opener, but they suffered a blow after 22 minutes when Darren Powell limped off and was replaced by Viafara.
The injury disrupted Southampton's rhythm and they paid the ultimate price minutes later as Andrew Surman gave the ball away to Nalis, who slid it to Halmosi and the Hungarian slotted home his second goal in two away games.
Plymouth almost doubled their lead immediate as Nalis played the ball into Halmosi again, but this time he shot wide.
However, the respite for Southampton only lasted a matter of seconds when Paterson picked the ball up and stroked in a superb effort from 25 yards.
Disgruntled home fans voiced their concerns as Davis made a superb save to stop Easter making it 3-0 just before the break.
Southampton came flying out the traps after the restart in search of a way back into the game and Saganowski headed over from a tight angle.
The home side continued to push forward and Saganowski set up Stern John, but his shot was deflected over.
The resulting corner was glanced on by Viafara into the path of Thomas, who blazed over from close range when he should have scored.
Minutes later, Davies headed straight at McCormick, before Saganowski fired wide from distance.
Southampton were looking dangerous and Jermaine Wright's pass picked out John, but he dragged his shot from the edge of the box just wide.
However, Plymouth almost made the game safe soon after when Paul Connolly played in Steven MacLean, but his low shot was saved by Davis.
Second-half substitute Teale then played in Connolly, but once again Davis was alert to produce a fine smothering save.
Southampton continued to press late on, but they ran out of steam as Plymouth held on for the win that took them within two points of the play-offs.
Teams:
Southampton Davis, Thomas, Davies, Powell (Viafara 22),Vignal, Wright, Euell (Idiakez 77), Surman, Saganowski, John,Wright-Phillips (Hammill 46).
Subs Not Used: Poke, McGoldrick.
Plymouth McCormick, Connolly, Timar, Anderson, Sawyer,Halmosi, Nalis, Abdou, Paterson (Teale 69), Easter (Mackie 82),MacLean.
Subs Not Used: Larrieu, Fallon, Wotton.
Booked: Connolly.
Goals: Halmosi 31, Paterson 33.
Att: 17,806
Ref: Gavin Ward (Surrey).