England captain Andrew Strauss set West Indies a mammoth target of 503 to win after declaring at 221 for eight at the Antigua Recreation Ground on Wednesday and then picked up three wickets as the hosts reached 143-3 at the close.
West Indies need a further 360 to win with Ramnaresh Sarwan 47 not out and Shivnarine Chanderpaul undefeated on 18.
Although the pitch in the hastily rearranged match has endured well, West Indies do not have a good record of batting for survival in recent years and England will be bitterly disappointed if they cannot turn their dominance throughout this test into victory.
"The way we have bowled in this series so far, sticking to our task, searching for reverse swing, and then we'll have a new ball before tea, I'm pretty confident we can do it," England fast bowler Steve Harmison told reporters.
England will, though, be hampered by a hip injury to Andrew Flintoff who was restricted to just three overs on Wednesday.
Opener Devon Smith was trapped lbw on the back foot by Harmison to break a promising first wicket stand of 59.
With huge responsibility on his shoulders, West Indies skipper Chris Gayle looked in good form as he moved to 35.
But, as in the first innings, a loose stroke cost him dear and he was rapped on the pads attempted to sweep Graeme Swann's off-spin.
At 81 for two, any thought of a record run chase, that would have to surpass their own world record fourth innings total of 418 at this ground six years ago against Australia, had surely been discarded by West Indies who were now in a simple survival battle.
Ryan Hinds' disappointing return to the West Indies side continued as he opted to try and drive Stuart Broad in the first over for the England seamer and managed only to give Owais Shah for a simple catch.
Sarwan was then joined by fellow Guyana batsman Chanderpaul and their solidity against some focused English bowling saw them through to the close.
Gayle, who conceded he was feeling "drained" said it was crucial that the pair make it through the morning session on Thursday.
"We know it is in England's favour at this point in time but having said that there are two experienced batsmen at the crease, the first session is very important and hopefully by the end of it those guys will still be at there," he said.
"I'm confident the guys can do it, it is going to be difficult, no one can say it will be easy but we have to have the self belief that the guys can get the job done," added the West Indies skipper.
A half-century from Alastair Cook provided the backbone of England's innings with Kevin Pietersen (32), utilising his controversial switch-hitting, and Paul Collingwood (34) chipping in with useful scores as the tourists stepped up the run-rate.
England (1st innings): 566-9 decl
West Indies (1st innings): 285
England (2nd innings) (overnight 31-1)
A. Strauss c Smith b Edwards 14
A. Cook c Smith b Hinds 58
J. Anderson c Ramdin b Powell 20
0. Shah b Powell 14
K. Pietersen c Ramdin b Benn 32
P. Collingwood b Hinds 34
M. Prior not out 15
S. Broad run out 1
A. Flintoff c Hinds b Benn 0
S. Harmison not out 7
Extras: (b-12, lb-3, w-5, nb-6) 26
Total: (eight wickets declared; 50 overs) 221
Fall of wickets: 1-23, 2-69, 3-97, 4-145, 5-189, 6-195, 7-201, 8-206.
Bowling: Edwards 9-1-36-1 (5nb, 1w), Taylor 9-2-34-0, Powell 7-0-33-2, Benn 14-1-58-2 (1nb), Hinds 11-1-45-2.
West Indies (2nd innings):
C. Gayle lbw b Swann 46
D. Smith lbw b Harmison 21
R. Sarwan not out 47
R. Hinds c Shah b Broad 6
S. Chanderpaul not out 18
Extras: (lb-4, nb-1) 5
Total: (three wickets, 45 overs) 143
Fall of wickets: 1-59 2-81 3-96
To bat: B. Nash, D. Ramdin, J. Taylor, S. Benn, D. Powell, F. Edwards.
Bowling: Anderson 9-2-24-0 (1nb), Broad 9-2-22-1, Swann 16-4-50-1, Harmison 6-0-17-1, Flintoff 3-1-12-0, Pietersen 2-0-14-0.