Crewe 2 Wigan 0
Goals from Rodney Jack and Nicky Maynard dumped last season's Carling Cup finalists Wigan out at the first hurdle, at Coca-Cola League One Crewe.
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Jack, in his second spell with the club, broke the deadlock just before half-time before Maynard rounded the game off right at the death.
The Latics, with five changes to the side that drew 2-2 at Everton at the weekend, had shaded the opening period but they were generally restricted to long-range efforts and never convinced in their search for an equaliser after the interval.
The introduction of Emile Heskey from the bench sparked hopes of a revival but Alex goalkeeper Ben Williams made some fine saves when called upon.
And the home side added gloss to a fine result as in-form Nicky Maynard steered in a second in injury-time.
It was a result that looked unlikely for most of the first half.
The Latics created the first opening in the seventh minute when youngster Tomasz Cywka laid off for Leighton Baines to whip in a cross from the left only for Andreas Johansson slice wide at the far post.
A couple of minutes later, Alex striker Nicky Maynard found space down the right and played the ball infield where Jack spun but Mike Pollitt held his firm shot.
Wigan's Gary Teale was having plenty of joy down the right against Billy Jones and his cross was headed straight at Williams by Paul Scharner before Denny Landzaat made the Alex goalkeeper work harder to hold a drive from 20 yards.
David Wright went close when Teale played him in on the right side of the area but the former Alex full-back could not guide his curling left-foot effort inside the far post.
Just before the break, Varney was in action at the other end, nipping in front of Fitz Hall to cross for Jack, who had a spell in the League of Ireland last year, to slam past Pollitt.
In the first minute after half-time, Varney should have made it two after racing onto a through ball from classy Wales international David Vaughan but the forward could not beat Pollitt at his near post.
The scorer of two goals against Everton at the weekend, Scharner forced a fine save from Williams after the ball sat up nicely for a half-volley from the edge of the area.
Baines saw a powerful drive pushed around the post by Williams but, as the second half wore on, a leveller looked less and less likely to materialise.
Having already brought on Arjan de Zeeuw and youngster Lewis Montrose, Wigan threw Heskey into the fray with 20 minutes left.
The former Liverpool man almost got to a powerful Teale cross but the ball was cleared by Neil Cox and Maynard blasted way off target after being immediately put through at the other end.
Heskey then got in behind Cox to prod Kevin Kilbane's cross goalward, only for Williams to tip the ball around the post at full stretch.
But, in added time, Varney was again played in behind the Latics defence down the left and he pulled back for Maynard to tuck away his eighth goal of the season. Teams:
Crewe Williams, Jones, Baudet, Cox, Otsemobor, Vaughan,Roberts, O'Connor, Varney, Maynard (O'Donnell 90),Jack (Rix 83).
Subs Not Used: Tomlinson, Higdon, Lowe.
Goals: Jack 42, Maynard 90.
Wigan Pollitt, Wright, Jackson, Hall (De Zeeuw 53), Baines,Teale, Scharner, Landzaat, Kilbane, Johansson (Heskey 71),Cywka (Montrose 63).
Subs Not Used: Filan, Owens.
Booked: De Zeeuw.
Ref: C Webster (Tyne & Wear).