Inspired by Scotland's independence referendum on September 18 and other restive minorities in Europe, and feeling the pinch from Italy's economic woes, strains in the century-old marriage are starting to show.
"We are not Italians," says Eva Klotz, 63, a local separatist politician, her office in the capital Bozen -- Bolzano in Italian -- adorned with a Scottish and a Catalan flag and a large Che Guevara poster.
"Italy is an occupying power, it has no right to govern our country ... We are following very closely indeed what happens with Scotland and (the Spanish region) Catalonia," she says.
Germanic in culture and language for centuries, South Tyrol was ceded after World War I by the Austro-Hungarian Empire to Italy, Rome's reward for entering the conflict on the winning side.
Italy's fascist leader Mussolini then sought to Italianise the area, moving in large numbers of Italians, banning the German language in schools and the civil service and forcing people to change their names.
"Il Duce" -- whose Roman emperor-esque image can still be seen on a frieze on Bozen's tax office -- and Hitler struck in a deal in 1939 whereby German-speakers could settle elsewhere in the Third Reich.
"We moved to Bavaria (in southern Germany) when I was six," remembers one who did, Sieglinde Taschler, a sprightly 79-year-old with bright blue eyes tending her garden outside Bozen.
"People there made fun of us, saying 'here come the Italians'."
After 1945, many of the 60,000 or so who had emigrated returned, and South Tyrol -- Alto-Adige or Sudtirolo in Italian -- remained part of Italy.
By the early 1960s, however, German-speakers' unhappiness erupted in a bombing campaign -- directed against electricity masts, not people - and it took UN intervention to settle the dispute.
The resulting 1972 agreement gave the area wide-ranging autonomy which survives to this day, giving the region powers to write its own laws in many areas. Some 90 percent of taxes paid are meant to be returned by Rome.
Economically, South Tyrol boomed, says Georg Lun, 41, from the Bozen chamber of commerce. Until the global financial crisis, it had full employment, profiting from its position between Italy and other parts of Europe.
"South Tyrol is doing very well indeed compared to other European regions. We have a gross domestic product of €36-37,000 ($48-49,000) per capita, putting it among the top 20 regions in Europe," he told AFP.
"We live in a wonderful place," Manuel Moro, 35, an engineer from South Tyrol's Italian community -- which make up around a quarter of the 510,000-strong population -- told AFP. "We should be happy."
But not everyone is, particularly since the eurozone crisis forced Italy -- now back in recession -- to cut spending and hike taxes to pay down its more than €2 trillion ($2.7-trillion) national debt.
South Tyrol no longer receives all the tax money that it should, taxes levied by Rome -- which decides their level -- have risen and the region has even been told to cut hospital beds, locals complain.
Corporate and income tax levels are among the highest in Europe, to say nothing of the huge amount of red tape. Higher fuel taxes mean that filling up your car costs some €20 more in South Tyrol than over the border in Austria.
The laws also keep changing.
"For firms there is no legal certainty," says Heinz-Peter Senoner, chairman of Bozen-based power firm Energie SpA AG. "Every day Rome announces new reforms.
The biggest local party, the South Tyrolean People's Party, which in 2013 lost its long-held absolute majority but remains in power, wants to stay part of Italy but is now pressing for "full autonomy", notably when it comes to tax.
But three parties with a combined 10 seats in the 35-MPs regional parliament want to cut ties completely, either to unify with Austria or to create a new independent country, possibly even with their blood brothers in the Austrian state of Tyrol.
"We want one Tyrol, one country, independent from Austria," pensioner Lorenz Mayer, 65, told AFP, showing off a "Suedtirol wird frei!" ("South Tyrol will be free!") sticker he keeps in his wallet.
But whether demanding independence is realistic is another matter, particularly with Italy, a unified country only since the 19th century, wary of stoking separatist sentiment elsewhere, for example in the Veneto region or in Lombardy in the north.
Austria, too, does not want to open up old wounds and embark on any "new adventures", said Florian Kronbichler, 62, a former magazine editor and now a Green MP representing South Tyrol in the Italian parliament.
Sieglinde Taschler, meanwhile, having seen it all, adopts a zen attitude.
"I'm nearly 80, I just want peace and quiet. All this nonsense about independence comes from politicians stirring things up," she says.