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Pratt has worked with Pink Floyd (also David Gilmour), Gary Moore, Roxy Music, Michael Jackson, Echo & the Bunnymen, Coverdale Page, Kirsty MacColl, The Smiths, Tears for Fears, Lemon Jelly, The Orb, All Saints, Icehouse, Madonna, Stephen Duffy, Robbie Robertson, Billy Pilgrim, A. R. Rahman, Whitesnake, Womack & Womack, and Toy Matinee. He is a member of The Transit Kings with Alex Paterson (of The Orb), Jimmy Cauty (of The KLF), and Dominic Beken. Cauty and Pratt also released "I Wanna 1-2-1 With You" as Solid Gold Chartbusters. Since 2006, Guy Pratt has also played bass for Bryan Ferry and is currently[when?] accompanying him on his solo tour throughout Europe.
Pratt rose to prominence when he was chosen as the bass player for Pink Floyd's post-Roger Waters Delicate Sound of Thunder and P*U*L*S*E world tours in 1987 and 1994. He co-performed the vocals in "Run Like Hell", "Another Brick in The Wall (Part 2)", "Us and Them" and "Comfortably Numb" with David Gilmour during the live shows. He also performed on several tracks on The Division Bell album, though most of the bass parts were performed by Gilmour. Tony Levin performed most of the bass parts on A Momentary Lapse of Reason, with Pratt replacing him on the accompanying tour due to Levin's unavailability.
He also toured as part of Pink Floyd guitarist David Gilmour's On an Island band, alongside another Pink Floyd member (and his father-in-law), Richard Wright.
Pratt has also composed music for TV and cinema. He produced, co-wrote and played bass, guitar and keyboards on the music for the 1998 Channel 4 drama series The Young Person's Guide to Becoming a Rock Star. With regular collaborator Dom Beken, he provided the theme music to Spaced. Pratt also appeared in Spaced, playing the character of Minty. He has also acted in Linda Green, and appeared in an episode of the remake of Randall & Hopkirk, starring Vic Reeves & Bob Mortimer. His father Mike Pratt played the part of Jeff Randall in the original 1960s series.
As a songwriter, he co-wrote the UK Number 1 hit "Ain't No Doubt", sung by Jimmy Nail.
In August 2005, Pratt's one-man music/comedy show, My Bass & Other Animals, debuted at the Edinburgh Festival. A book, based on the show, was published in May 2007. He is also a regular in the backing band for the BBC Radio 2 comedy music programme Jammin' with Rowland Rivron
On April 2010, Guy Pratt joined Argentinian band The End Pink Floyd, with Durga McBroom and Jon Carin, in Buenos Aires, Argentina. On 13 June 2011, Pratt joined The Australian Pink Floyd Show on stage for the Hampton Court Palace Festival for the song 'Run Like Hell'.
He spent 2011 performing stand-up in Switzerland, Australia, and at the Edinburgh Fringe, as well as on a South American tour playing Bass for Dominic Miller.
On 9 November 2013, Guy joined the UK Pink Floyd cover band Brit Floyd on stage as a special guest during the Liverpool leg of their "Pulse" tour. He performed on the songs "One of These Days", "Comfortably Numb" and shared lead vocals with band front man Damian Darlington during the finale of "Run Like Hell".