Four protestors were chained to tracks a few hundred metres from Caen station in northwestern France, activists said, shortly after the train departed for Gorleben in Germany.
Protestors unfurled a banner reading, “Our resistance knows no borders,” said a statement from the Ganva non-violent anti-nuclear group.
“This nuclear convoy, the most radioactive ever, exposes the population to excessive risks. There is a risk to lives in the short term in case of an accident, but also a long-term the risk to their health,” the statement said.
The train, which environmental lobby groups say is carrying waste with twice the radioactivity of the Chernobyl disaster, is headed to Gorleben in Germany.
The waste is on its way back to Germany - where it was initially created in the generation of electricity - after being treated at a plant in France by nuclear giant Areva. It consists of 14 carriages: 11 with waste and three with riot police.
Areva spokesman Christophe Neugnot called criticism from groups such as Greenpeace “a smokescreen for anti-nuclear protestors to hide the fact that nuclear energy is taking off again in almost all European countries.”
He dismissed concerns about possible leaks in transit, describing the train as a “fortress on wheels. The containers would survive a train hitting them at full speed.”
Areva has also rejected the “most radioactive” tag, insisting the cargo is not as radioactive as the last load of waste they shipped back to Germany.
Around 30,000 demonstrators are expected to oppose the train's arrival in Germany, where around 16,000 police have reportedly been mobilised to deal with protests.
Areva says the waste is equivalent to that generated annually by the nuclear-generated electricity used by 24 million Germans. The waste has been stabilised by being melted and mixed into glass cylinders, which are stored in Castor containers.
Environmentalists say that the intermediate waste storage facility at Gorleben in northern Germany is not appropriate.
“We're not here to prevent the train leaving. The waste has to return to Germany but not to Gorleben, which is not an appropriate site. No one has a solution for this waste,” Greenpeace France's Pascal Husting told AFP.
“How can you imagine that it will still be remembered in 6,000 generations, or the time the waste will take to become safe, where it is stored,” said another Greenpeace activist who asked not to be named.
German lawmakers last week approved a bill extending the life of the country's 17 reactors by 12 years, although they were due to come offline in 2020. Opinion polls show that most Germans were against parliament's decision.
The convoy is the 11th of its kind to be sent back to Germany.
Almost 16,000 police were deployed in Germany for the previous such convoyin 2008, which protestors held up for 14 hours at the border.