Reports said a lorry shunted a family car into the back of a tanker truck, causing it to explode on the A21 near Brescia.
The lorry driver died as did three adults and the two children who were travelling in the car.
The Kia car had a French number plate according to reports quoted by AFP news agency.
Italian TV said the crash happened as traffic on the motorway was backing up because of an earlier accident.
Smoke from the explosion could be seen for several miles. (Courtesy BBC)