The star of 'Wall Street' and the Welsh-born actress have suffered a number of setbacks in recent years. Douglas (68) was diagnosed with throat cancer in 2010, and Zeta-Jones (43) has revealed that she suffers from bipolar II disorder.
The couple had not been photographed publicly together since a gala event in Manhattan in April, which had led to rumours of a split.
Last week Douglas was seen playing golf in Sardinia while his wife stayed at home in New York.
On Tuesday night, Douglas, looking relaxed and dressed in white, dined with friends at a restaurant in Nice. Later this week he is due to attend the Deauville American Film Festival in France.
It is the same festival where he was introduced to Zeta-Jones by his friend, the actor Danny DeVito, in 1998.
A spokesman for Zeta-Jones said: "Catherine and Michael are taking some time apart to evaluate and work on their marriage."
They made the decision at around the time that Douglas said his throat cancer had been caused by oral sex. Those close to the couple said neither had filed for divorce, nor moved towards a legal separation, and friends still held out hope that they could work out their differences.
One said: "They want the best for their kids, no matter what happens."
Douglas and Zeta-Jones married in 2000 and have two children, Dylan (13) and Carys (10).
The couple are thought to have signed a prenuptial agreement that would entitle Zeta-Jones to millions of dollars in a divorce. When Douglas divorced from his ex-wife Diandra after two decades in 2000, he handed over $45m (€34m).