As well as serving as a bellwether for Merkel and her euro crisis-busting strategy, elections in North Rhine-Westphalia (NRW) state, home to 18 million people, have also sparked major political upheavals in the past.
The snap poll - Germany's third regional vote in eight weeks - sees Merkel's conservatives fighting to rout the centre-left Social Democratic Party (SPD) and coalition partners, the ecologist Greens.
Polls show the SPD leading the race with about 38 percent compared to just over 30 percent for Merkel's Christian Democratic Union (CDU), but a third of the more than 13 million eligible voters are still undecided.
The CDU's chief whip, Peter Altmaier, said he hoped for a good NRW result and added that polls showed Merkel and her policy on Europe enjoyed wide support among voters generally.
"We nevertheless hope to get the best possible result for the CDU and every additional vote for the CDU is also support for our national policy," he told reporters.
SPD state premier Hannelore Kraft, is facing off against Merkel's Environment Minister Norbert Röttgen, and hopes to avoid a repeat of the knife-edge result of two years ago.
Although the SPD and Greens saw off a centre-right alliance in the state that mirrored Merkel's national coalition, Kraft could only form a minority government.
And after just 22 months in power, her state government fell when the regional parliament failed to pass a draft budget.
Although the media is keen to read NRW entrails for signs about next year's election, analysts said they did not see the regional vote directly impacting on Merkel.
"I see no change. There's no mood for change in the state," Volker Kronenberg, politics professor at Bonn University, told AFP, calling it an "almost completely" issue-less campaign that had focused more on personalities.
He added that although a poor showing by the CDU in NRW would be "painful" for Merkel, unlike last year's disastrous defeat in Baden-Württemberg state after nearly six decades of conservative rule, it would have little consequence.
Nils Diederich, a political scientist at the Free University in Berlin, agreed.
"The (national) opposition SPD's power is weak and the CDU is surprisingly stable," he said.
NRW has seen violent clashes in the run-up to Sunday's vote after campaigning by a small extreme-right party, Pro-NRW, using cartoons of Mohammed outside Mosques led to clashes between ultra-conservative Islamic Salafists and police trying to keep the peace.
The state historically plays a big role in federal politics - in 2005, a lost vote in NRW prompted then Chancellor Gerhard Schröder to call a snap federal election which saw Merkel wrest power from him.
Bordering the Netherlands and Belgium, NRW is a major industrial base.
Once known as the "land of coal and steel" helping to power the country's post-World War II economic miracle, both sectors have since declined but other industries such as mechanical engineering and metal and iron-working have grown.
Fresh from an electoral boost last Sunday in northern Schleswig-Holstein state, the pro-business Free Democratic Party (FDP), a junior ally in Merkel's coalition, is set to garner about six percent, according to polls.
Although a far cry from its near 15-percent peak in the 2009 federal election, this result would secure entry into the state parliament and would be better than its backing in recent nationwide surveys.
A poor result for the FDP on Sunday could possibly destabilise the ruling federal coalition, analysts say.