French President Francois Hollande voiced hope that Britons "will remember" their close ties to Europe when they vote in a June 23rd referendum on EU membership.
"We are as united as we have ever been," Hollande said after joining the ceremonial first train ride through the world's longest tunnel.
"I hope that the British will remember (that closeness) when the day comes" to cast their vote, he said.
In March, Hollande warned that a British exit from the 28-nation bloc would have an impact "in many areas," including the single European market, the financial sector and bilateral economic ties.
On Wednesday Hollande drew a parallel between the construction of the 57-kilometre Gotthard Base Tunnel with another trailblazing project, the Channel Tunnel.
The 50-km link, which opened in 1994, means that London and Paris are less than three hours apart by high-speed rail, a closeness that has woven many ties in business, tourism and culture.
"Nobody imagined that it would be possible one day to travel from France to England in this way," Hollande said.
On Monday, a poll published for The Guardian newspaper showed the "leave" vote at 52 percent against 48 percent for staying.
A Brexit could have an impact for Switzerland's own relationship with the EU.
The alpine country is currently grappling with how to implement stricter immigration controls -- approved by the public in a referendum in 2014 -- whilst maintaining its bilateral agreements with the EU, one of which is the free movement of people.
Negotiations between Switzerland and the EU are currently on hold until the outcome of the British referendum is known.
Speaking at the Gotthard opening ceremony on Wednesday Swiss president Johann Schneider-Ammann said: "We must have clarification on bilateral relations."
Schneider-Ammann travelled with Hollande, German chancellor Merkel and Italian prime minister Matteo Renzi in a first-class carriage on one of the first trains through the new tunnel, which offered the leaders the chance to discuss matters in a "relaxed manner", said news agencies.
Merkel told ATS it was "marvellous" to think about taking a journey with 2,000 metres of mountain rock above her head.
The tunnel was entirely funded by non-EU member Switzerland, but leaders from the bloc have hailed it for improving connectivity from Rotterdam to the Adriatic at a time when the continent's divisions have dominated headlines.
With Europe's political unity shaken by a massive migrant crisis and the looming threat of Britain's EU exit, Schneider-Amman said the tunnel would "join the people and the economies" of Europe.