The E3 is a mini Tour of Flanders which includes 13 climbs on the 201km route which starts and finishes in Harelbeke.
The peloton tackle the mythical Muur, excluded from next Sunday's Tour of Flanders, at the 100km mark followed by six quickfire ascents, the last of which is the Taaienberg with maximum ramps of 18 per cent.
Three more climbs follow before the pivotal Kwaremont and Knokteberg ascents which precede the 13th hellingen – the Tiegemberg - before a 13km run-in to the finish.
Cancellara took his second consecutive victory at Harelbeke last year after a long solo break and the Swiss has shown his form this season with wins at Strade Bianche and in the time trial at the Tirreno–Adriatico.
"This is the first time the (RadioShack) guys will have a real leader for the classics," Cancellara, who was pipped to victory by Simon Gerrans in last week's Milan-San Remo, said.
"Everyone is super-motivated. I am excited about the coming races. I think we’re going to put on a big show for everyone."
Spartacus will face a strong challenge from home favourite and four-time former winner Tom Boonen (Omega Pharma-Quickstep) and Philippe Gilbert (BMC).
Greg Van Avermaet and Alessandro Ballan (BMC Racing), Heinich Haussler and Johan Vansummeren (Garmin-Barracuda), 2009 Harelbeke winner Filippo Pozzato (Farnese Vini-Selle Italia) plus Bjorn Leukemans and Stijn Devolder (Vacansoleil-DCM) will also fancy their chances.
4 Rik Van Looy BEL 1964, 1965, 1966, 1969
4 Tom Boonen BEL 2004, 2005, 2006, 2007
3 Jan Raas NED 1979, 1980, 1981
2 Eddy Planckaert BEL 1987, 1989
2 Johan Museeuw BEL 1992, 1998
2 Andrei Tchmil MDA, BEL 1994, 2001
2 Fabian Cancellara SUI 2010, 2011
2011 Fabian Cancellara (SUI) Jürgen Roelandts (BEL) Vladimir Gusev (RUS)
2010 Fabian Cancellara (SUI) Tom Boonen (BEL) Juan Antonio Flecha (ESP)
2009 Filippo Pozzato (ITA) Tom Boonen (BEL) Maxim Iglinskiy (KAZ)
2008 Kurt-Asle Arvesen (NOR) David Kopp (GER) Greg Van Avermaet (BEL)
2007 Tom Boonen (BEL) Fabian Cancellara (SUI) Markus Burghardt (GER)
2006 Tom Boonen (BEL) Alessandro Ballan (ITA) Aart Vierhouten (NED)
2005 Tom Boonen (BEL) Andreas Klier (GER) Peter Van Petegem (BEL)
2004 Tom Boonen (BEL) Jann Kirsipuu (EST) Andris Nauduzs (LAT)
2003 Steven de Jongh (NED) Steffen Wesemann (GER) Stijn Devolder (BEL)
2002 Dario Pieri (ITA) Jo Planckaert (BEL) Johan Museeuw (BEL)