Oxford captain Salil Oberoi led the way with a century as his side edged into a 12-run lead in The Parks.
Oberoi's fluent 115 off 148 balls was in contrast to much of the scoring on a day of attritional cricket.
But with four wickets in hand, it is Oxford who hold all the aces at the halfway stage.
Oberoi, who hit a double hundred in last year's Varsity Match, said: "I'm very pleased to get another ton, but I should have played more for the side.
"I didn't feel that I was going to get out to their bowling, but I threw away my wicket.
"I think they wanted to block my boundaries as soon as I went in as they immediately had sweepers out for me.
"There were no slips so there was no pressure on me to get singles.
"They didn't bowl too many loose balls. It was only after lunch that I had a spell where I was scoring quickly."
Oberoi smashed 19 fours in his innings after coming in at 48-1.
Peter Dunbar was the second wicket to fall when he gave a silly run-out opportunity to Matthew Austin.
At 213-5, Cambridge may have sensed a chance, but some soilid batting from Nick Hillyard (57 not out) and Chris Stearn (38), who put on 80 for the fifth wicket, maintained Oxford's advantage.
Cambridge captain Tom Savill bowled with energy for his 4-87, while left-arm spinner Vikram Banerjee toiled away in the sun for 31 overs without a wicket.
Oberoi said: "It could have been better, but I'm pleased with where we are. I would like a lead of 120-plus.
"The more time we take, the less time Cambridge have to set us a target.
"We'll just keep going on Wednesday and hop
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