The global PR and public affairs firm already has a German office in Berlin.
Isabel Kassabian, the deputy MD of APCO in Germany, will relocate from the country's capital to what is her home city in the coming weeks to set up the new base.
Kassabian, who joined the firm in 2002 and has held her current role since 2015, said the leading industries of Frankfurt were healthcare, financial services, ICT and transportation.
Said global CEO Brad Staples: "As Germany has become increasingly important on the international stage over the past two decades, Frankfurt has become an even more significant global hub for business.
"While as a firm we remain confident about the future of London as a global financial centre, it obviously makes sense in the post-Brexit vote environment to ensure APCO has a strong presence in all Europe’s key financial capitals."
APCO had 680 staff globally and was the world's 18th largest PR firm at the end of 2015, according to the 2016 PRWeek Global Agency Business Report. The MD of the firm's Brussels office recently became its new Europe chair.