The pair's latest cut 'Scream & Shout' is currently 5,000 copies ahead of James Arthur's 'Impossible' on the midweek chart.
The feat would mark Spears's first chart-topper in the UK since 2004's 'Everytime', while it would mark will.i.am's second consecutive number one single from his #willpower album.
Taylor Swift is up to three with 'I Knew You Were Trouble', Rihanna is at four with 'Stay' and Bruno Mars completes the Top 5 with 'Locked Out of Heaven'.
Bon Jovi land at 20 with their new single 'Because We Can', BBC Sound of 2013 winners Haim are up to 29 with 'Don't Save Me' and Jay-Z and Kanye West's 'Clique' re-enters at 34.
However, despite hitting number one on the iTunes sales chart, David Bowie's surprise comeback single 'Where Are We Now?' has not landed in the Top 40.
This is because a large number of the tracks downloaded are not eligible to chart as they have been given away to consumers who pre-order Bowie's new album The Next Day, and the Official Charts Company has said it is "not possible to distinguish album sales from track sales from the retail data received".
Calvin Harris slips to two with 18 Months, Jake Bugg is at three with his self-titled debut, Rihanna is at four with Unapologetic and Ed Sheeran is at five with +.
Watch the music video for will.i.am and Britney Spears's 'Scream & Shout' below: