The regulator said the bank's conduct was "unacceptable" and it found "significant weaknesses" in the systems and controls in Barclays' Investment Banking Division between November 2007 and January 2012.
The bank has been penalised for "failing to properly protect clients' custody assets" worth £16.5 billion.
Barclays escaped an even larger fine – just under £54m – by settling early.
David Lawton, FCA director of markets, said: "Safeguarding client assets is key to maintaining market confidence if firms fail - Barclays lack of focus on the rules was unacceptable.

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"Our on-going scrutiny of firms' compliance reflects the importance of the regime, which protects custody assets worth £10 trillion held in the UK."
The FCA said clients risked incurring extra costs, lengthy delays or losing their assets if Barclays had become insolvent.
Neither the FCA or or its predecessor the FSA have imposed a fine so high for this particular breach.
Tracey McDermott, FCA director of enforcement and financial crime, said: "Barclays failed to apply the lessons from our previous enforcement actions, numerous industry-wide warnings, and exposed its clients to unnecessary risk.
"All firms should be clear after Lehman that there is no excuse for failing to safeguard client assets."
She said: "The FCA's rules are there to protect client assets if a firm becomes insolvent. Barclays failed to properly apply these rules when opening 95 custody accounts in 21 countries.
"As a result, Barclays' records did not correctly reflect which company within its Investment Banking Division was responsible for the assets in the accounts. Barclays also failed to set up appropriate legal arrangements with these companies.
"These failings were compounded by flaws in account naming or incorrect data that suggested assets belonged to Barclays instead of its clients.
"This breached the FCA's Client Asset Rules and requirements that firms should have adequate management, systems and controls (Principle 3) and properly safeguard clients' assets (Principle 10)."