France's Total, Norway's Statoil and Italy's ENI have announced they will stop their activities to evade the penalties which target companies doing business with the Middle East country.
Japanese oil explorer Inpex Corp has also said it could pull out of an oil field project, despite not being named on a U.S. list targeted for the sanctions.
The U.S. has increasingly tightened sanctions against Iran over concerns about its nuclear programme and whether it is attempting to acquire nuclear weapons.
Tehran has repeatedly insisted the programme is purely for peaceful purposes.
Japanese trade minister Akihiro Ohata said: 'Inpex is considering things including a withdrawal based on its own management judgement.
'I want to respect their business decision and refrain from interfering in the matter.'
Inpex has a 10 per cent stake in the Azadegan oil field project and could struggle to raise funds from U.S. financial institutions and global development projects if it was subject to sanctions.
The Azadegan field was Iran's biggest oil find in 30 years when it was discovered in 1999 - with estimated reserves of 26 billion barrels and available resources believed to be around six billion barrels.
Naftiran Intertrade Co, a subsidiary of the National Iranian Oil Company based in Switzerland, will face new sanctions.
The field started partial output in 2008.
Recent legislation gives the U.S. administration the power to penalise foreign companies which invest more than £12.7m in Iran's energy sector.
However, companies taking steps to comply with the law are exempted from penalties.
'People are increasingly reaching the conclusion that it's simply not worth it to engage in activities with Iran,' Deputy U.S. Secretary of State James Steinberg said.