Sky News is forecasting that Scotland has rejected independence, meaning the United Kingdom will remain intact.
Victories in Glasgow, Dundee and West Dunbartonshire had given the Yes campaign a major boost.
However, they were followed by substantial No victories in Stirling, Aberdeen and Dumfries and Galloway.
Scotland First Minister Alex Salmond tweeted: "Well done to Glasgow, our commonwealth city, and to the people of Scotland for such a incredible support."
David Cameron tweeted: "I've spoken to Alistair Darling - and congratulated him on a well-fought campaign."
Voters sided with the Better Together team in the Western Isles (10,544 to 9,195) and Clackmannanshire (19,036 to 16,350) - both key Yes targets.
The No strongholds of Shetland (9,951 to 5,669) and Orkney (10,004 to 4,883) saw the voters reject independence.
Mr Cameron is due to make a live TV address to the nation from 10 Downing Street once the result is confirmed.
The Prime Minister is expected to set out not only proposals to devolve more powers to the Scottish Parliament, but also significant changes for other parts of the country.
The referendum looks set to break records for turnout, with figures as high as 91% in East Dunbartonshire, 90.4% in East Renfrewshire and 90.1% in Stirling.
A poll taken by YouGov after people voted predicted a victory for No by 54% to 46% for Yes.
And even before the first results were announced, its president Peter Kellner told Sky News: "I can't see No losing this now.
"At the obvious risk of looking like a complete prat in eight hours' time, I would say it is a 99% certainty of a No victory."
Speaking on Sky News, Blair McDougall, the Better Together campaign director, welcomed the high turnout.
"There has been the biggest super-poll in Scottish political history today with probably the biggest turnout in recent political history."
Sky News has learned officials at the referendum count in Glasgow are investigating 10 cases of suspected electoral fraud at polling stations.
Although the votes are being counted at 32 regional centres - whichever side "wins" in each area is irrelevant.
All that matters is whoever gets the most overall - even if it is by a single vote.
:: Watch live: Scottish referendum coverage now on Sky News Sky 501, Virgin Media 602, Freesat 202, Freeview 132.
:: Live coverage is also available on sky.com/news and Sky News for iPad and on your mobile phone.