A first convoy of US weapons-grade plutonium is on its way from northern France to a processing plant in the south-east of the country.
Police are guarding bridges along the route south
A heavily-guarded truck left a nuclear facility at La Hague, where the 125kg shipment had been stored overnight.
Environmentalists, who have protested against the consignment, say it might be vulnerable to terrorist attack.
The state-owned company which will reprocess it says the consignment is safe and will be converted into fuel.
The treatment is part of a post-Cold War agreement between the United States and Russia to get rid of plutonium from excess nuclear warheads.
The 125kg (275lb) of radioactive material reached Cherbourg aboard two armed British freighters early on Wednesday.
It was then loaded onto lorries and driven to the plant in nearby La Hague, accompanied by a heavy police escort.
The plutonium has been in transit since the two British-registered ships left South Carolina last month.
It is now being driven nearly 1,000km (660 miles) to south-east France for further reprocessing at the Cadarache facilities run by the Areva-Cogema company.
Police are guarding all the bridges along the route.
But environmental campaigners Greenpeace still have concerns.
"This is a high-risk strategy being played by the nuclear industry with the lives of millions of people," said Shaun Burnie, of Greenpeace International.
Some activists have called for a rally at the Cadarache plant on Thursday. In order to combat a repeat of protests in Cherbourg, a French court has ruled that any protester who goes within 100 metres of the shipment faces a 75,000 euro fine.
The French state-owned nuclear energy firm Areva, whose Cogema unit will recycle the plutonium into nuclear fuel, insists the shipment is safe.
"The plutonium... is shipped in casks that comply with the regulation of the International Atomic Energy Agency (IAEA)," Areva said in a statement. "Its transport is the object of the strongest safety and security measures."
Cogema will process the material and convert it into mixed oxide nuclear fuel (MOX), which will then be shipped back to the US for civilian use.
The US Department of Energy says the plutonium has to be shipped overseas because there is not a plant capable of carrying out the conversion process in the US.