The Chancellor said independence would force Scotland to adopt new currency arrangements, which would be a "very deep dive into uncharted waters".
The Scottish government has outlined plans to keep the pound if the country becomes independent after next year's referendum.
But in a new report, the Treasury said the economic case for creating a "sterling zone" was not clear and cast doubt on whether a deal could be reached.
Mr Osborne, launching the report in Glasgow, said the analysis showed the imperative to agree a currency union would be less strong for the UK than for Scotland.
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