A Neil Danns double killed off dozy Derby as League One Colchester pulled off a minor FA Cup shock at Layer Road.
Most bookmakers made Colchester, who dumped out Sheffield United in the last round, favourites to progress on the back of their fine recent run and Derby's wobbly form, and they did not disappoint with 23-year-old former Blackburn trainee Danns enhancing his blossoming reputation with his 12th and 13th goals of the season.
Richard Garcia added to Derby's woes and despite Tommy Smith's late penalty Phil Brown's outclassed side have nothing but a battle for Championship survival to look forward to for the rest of the season.
Just seven places separated the sides at kick-off, with Phil Parkinson's men lying second in League One and Derby floundering in 19th.
Injuries forced Parkinson to field a young rearguard with teenager Garry Richards and Pat Baldwin, 23, in front of 20-year-old Dean Gerken in goal while Brown handed a debut to former Southampton right-back Tomasz Hajto.
A nervy start from Hajto saw on-loan Tottenham winger Mark Yeates rob the Pole and force Lee Camp into an early save, before Garcia fired wide following a fine ball from the impressive Greg Halford. Inigo Idiakez then grazed the bar, but the referee's whistle had already been blown for a foul on Richards, before the Spaniard forced a smart save from Gerken with a neat volley.
Halford sent in a rasping drive which Camp did well to palm around his left-hand post before the Rams suffered a blow when Paul Peschisolido, who insisted on leading the line despite his wife Karren Brady's health problems, limped off shortly before the break.
Derby's lack of strikers was painfully illustrated by his replacement - 37-year-old assistant manager Dean Holdsworth.
And they fell after 44 minutes when Chris Iwelumo got a touch on John White's throw-in and Danns was on hand to smash the ball home from 10 yards.
Danns doubled Colchester's advantage in the 52nd minute when the Rams failed to clear another long throw.
Garcia's initial shot was blocked by Andrew Davies but midfielder Danns was once again first to the loose ball to hit a remarkable seventh goal since the turn of the year.
And six minutes later Colchester, who famously dumped mighty Leeds out of the competition back in 1971, ended the game as a contest when Garcia's header from the impressive Halford's cross was parried by Camp.
Australian Garcia, a former West Ham youngster, slid in to steer the rebound past the helpless keeper to seal United's 18th win in 20 games.
Derby grabbed a 79th-minute consolation from the spot after Halford sent Lee Holmes tumbling, Smith stepping up to send Gerken the wrong way.
But it was the hosts who nearly hit the net again when sub Gareth Williams was denied by Camp as they played out a thoroughly-deserved victory safe in the knowledge that none of the competition's big guns will fancy a trip to Layer Road in the next round.
Teams:
Colchester Gerken, Duguid, Baldwin, Richards, White, Halford,Danns, Izzet, Yeates (Williams 78), Iwelumo,Garcia (Stockley 77).
Subs Not Used: Guy, Elokobi, Cousins.
Booked: Yeates.
Goals: Danns 44, 52, Garcia 59.
Derby Camp, Hajto, Davies, Nyatanga, Michael Johnson,Bisgaard, Thirlwell, Bolder (Holmes 59), Smith, Idiakez,Peschisolido (Holdsworth 38).
Subs Not Used: Poole, Jackson, Edworthy.
Booked: Thirlwell, Holdsworth.
Goals: Smith 79 pen.
Att: 5,933
Ref: B Curson (Leicestershire).