The Prime Minister addressed a Confederation of British Industry (CBI) dinner at the Hilton Hotel and said the economy and the opportunities of a larger UK market is a major reason for a No vote.
He said many industries in Scotland are financed by investors from other parts of the UK and the vast majority of Scottish exports are to England.
He littered his speech with iconic and modern Scottish products and said an inter-connected economy benefits them all and protects the jobs of the workers who produce them.
Mr Cameron said: "This is one of the oldest and most successful single markets in the world.
"A market in which salmon farmed in the lochs of Argyll is served in the restaurants of Belfast.
"Whisky from Arran is sipped in the pubs of London and energy from the hills of Dumfries powers the homes of Cardiff.
"Scotland does twice as much trade with the rest of the UK than with the rest of the world put together, trade that helps to support one million Scottish jobs."
He told the audience of business leaders that business in Scotland benefited from the investment of others and it has allowed some to grow to be world leaders in their field.
He said: "Just look at some of the start-up businesses that are making waves around the world.
"Take the renewables firm Aubin. It's based in Aberdeen, but its investors are from Birmingham.
"Take video games company Outplay. It's based in Dundee, but it is funded by investors in Oxford.
"The point is, they may be located in Silicon Glen, but they're backed by the rest of the UK. "
Mr Cameron said independence would see a tougher marketplace for those companies.
He added: "Look at Scottish Power: it doesn't just generate power for Scotland - it generates electricity for Merseyside and Wales, too.
"Look at Irn-Bru: it isn't just made in Lanarkshire, it is made down in Milton Keynes as well.
"That is what an interconnected economy looks like - an economy of opportunity.
"But if we pull that apart, if we make foreigners of our neighbours, business becomes tougher, trade becomes more costly and complex, and jobs become harder to find."
Mr Cameron added: "My case is this: Our single market is one of our Union's greatest advantages.
"If we stay together, Scottish businesses have better opportunities, Scottish consumers have more choice and Scottish people have more secure jobs.
"Why put that great advantage at risk by going into the great unknown?"
Mr Cameron was also given a warning, by the CBI President, over the possibility of Britain withdrawing from the EU.
Sir Mike Rake, said: "We accept that calling a referendum on EU membership is a constitutional issue for government, but the ambiguity has already, and is increasingly, causing real concern for business regarding their future investment.
The CBI was criticised for giving a platform to only one side of the independence debate.
Patrick Harvie, Green MSP for Glasgow, said: "Staging a dinner with David Cameron rather than a balanced debate makes clear their position as a right-wing partisan lobby group.
"Businesses in Scotland are rightly interested in what independence could mean for them but they deserve to hear a range of views. Scottish Greens see huge opportunities for Scotland to grow a greater variety of businesses, and more sustainable economic policies.
"The CBI's austerity cheerleading, demand for privatisation of public services and continued bleating about tax cuts for highly profitable firms must be challenged, and I believe a Yes vote gives Scotland the opportunity to do just that."