Policies regarding Tehran's nuclear programme will prove contentious.
Powell exposed splits with Europe at the start of his trip to Brussels on Tuesday.
He said the EU’s evaluation that Tehran had been "honest" with the world’s nuclear watchdog - the International Atomic Energy Agency (IAEA) - was far too optimistic.
Powell told reporters: "I wouldn't have gone quite as far" - in reference to the judgement on Iran's cooperation with the IAEA presented on Monday by top EU foreign policy chief, Javier Solana.
The issue is set to come to a head on Thursday when the IAEA governing board meets in Vienna to consider Tehran's alleged attempts to develop nuclear weapons.
Powell reaffirmed on Monday that an IAEA report proved Iran had been seeking to develop atomic weapons.
The assertion was not contained in the report and was apparently not shared in Europe.
Javier Solana and the EU have a
different relationship with Iran
Powell added: "It confirms what the United States has been saying for some time... that the Iranian nuclear development programme was for more than just the production of power."
Other contentious issues
However, there are plenty of other new and old issues that are likely to surface in meetings with Solana and European foreign ministers.
Genetically modified food, the International Criminal Court and the “road map” Middle East stalemate all burst into the open at a EU-US summit in Washington in June.
But since then, new problems have cropped up as the EU forges ahead with a common defence structure - which Washington believes could undermine NATO, a row over US steel tariffs and the split over Iran's nuclear programme.
Powell was to hold in-depth discussions with Italian Foreign Minister Franco Frattini, whose country currently holds the rotating EU presidency, as well as EU External Affairs Commissioner Chris Patten.
These talks would be a chance for Powell to review Iraq and Afghanistan stabilisation efforts, the “War on Terror” , nuclear proliferation, the Middle East and the Balkans, according to State Department spokesman Adam Ereli on Friday.