Rotherham United go top of League One
The Millers made it four wins in a row against a promotion rival after a devastating first-half display saw them lead 3-0.
Kyle Vassell scored a double and Richard Wood made it three, which made Marcus Browne's second-half effort for Oxford nothing more than a consolation.
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Hide AdA strong start was rewarded with a 16th minute opener for Vassell, who was in the right place to turn home Chiedozie Ogbene's perfect cross.
Vassell got another, his fourth in four games, with a superb lobbed finish after 33 minutes.
Wood capped a perfect first-half performance when he scored a trademark header in time added on.
Oxford, who won 3-0 at Rotherham earlier in the season, improved after the break and got one back through debutant loanee Marcus Browne in the 71st minute.
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Hide AdThe Millers weathered a storm and held out for a brilliant win which leaves them top of the pile.
Oxford: Eastwood, Long, Dickie, Moore, Ruffels, Brannagan (Browne 46), Gorrin (Holland 46), Baptiste, Sykes, Mackie (Taylor 61), Fosu. Unused subs: Stevens, Hall, Taylor, Mousinho, Holland, Kelly.
Rotherham: Iversen, Olosunde, Ihiekwe, Wood, Wiles, Adelakun (Lindsay 71), Crooks, Barlaser (Clarke 90), Ogbene, Vassell (Ladapo 76), Smith. Unused subs: Bilboe, Hastie, Lamy, Kayode
Referee: David Webb.
Attendance: 8,077 (894)