Police cars were set alight and stones were thrown in a protest against the opening of a new base for the European Central Bank (ECB).
Violence broke out close to the city’s Alte Oper concert hall hours before the ECB building’s official opening.
Thousands of “Blockupy” activists were due to take part in a rally.
Organisers were bringing a left-wing alliance of protesters from across Germany and the rest of Europe to voice their anger at the ECB’s role in austerity measures in EU member states, most recently Greece.
The bank, in charge of managing the euro, is also responsible for framing eurozone policy and, along with the IMF and European Commission, has set conditions for bailouts in Ireland, Greece, Portugal and Cyprus.
Police set up a cordon of barbed wire outside the bank’s new 185m (600ft) double-tower skyscraper, next to the River Main.
But hopes of a peaceful rally were dashed as clashes began early on Wednesday.
Tyres and rubbish bins were set alight and police responded with water cannon as firefighters complained they were unable to get to the fires to put them out. One fire engine appeared to have had its windscreen broken.
Activists said many protesters had been hurt by police batons, water cannon and by pepper spray.
Police said as many as 80 of their officers had been affected by pepper spray or an acidic liquid. Eight suffered injuries from stone-throwing protesters.
Police spokeswoman Claudia Rogalski spoke of an “aggressive atmosphere” and the Frankfurt force tweeted images of a police van being attacked. They were braced for further violence as increasing numbers of activists arrived for the rally.
Blockupy accused police of using kettling tactics to cordon off hundreds of protesters and appealed for supporters to press for their release.
Europe-wide alliance of left-wing parties, unions and movements
Vehemently against austerity polices of European Commission, ECB and IMF
First Frankfurt protest attracted thousands in 2012
Activists from Greece’s radical left governing party Syriza and Spain’s anti-corruption Podemos are joining the rally
Also includes Germany’s Die Linke and Occupy Frankfurt
Rallying call: “They want capitalism without democracy, we want democracy without capitalism”
As the number of protesters grew in the streets away from the new ECB building, the bank’s president, Mario Draghi, gave a speech marking its inauguration.
The new headquarters, which had been due to open years earlier, cost an estimated €1.3bn (£930m; $1.4bn) to build and is the new home for thousands of central bankers.
Blockupy activists said on their website that there was nothing to celebrate about the politics of austerity and increasing poverty.