The pivotal election is aimed at breaking the bitter deadlock over the issue of secession. But neither side is likely to win a clear majority in the new regional parliament, setting up the scenario of long and challenging negotiations to form a new Catalan government.
Opinion polls have shown fugitive and jailed separatist candidates neck-and-neck in opinion polls with unionists, who claim to be in the best position to return Catalonia to stability and growth.
But with a record turnout expected, the outcome could hinge on the more than one-fifth who are undecided among Catalonia's 5.5 million eligible voters.
The nearly 2,700 polling stations will remain open until 8 p.m. (1900 GMT), with results expected a few hours later.
Weeks of campaigning involved little debate about regional policy on issues such as public education, health or housing. At the heart of the battle was the sensational recent independence push that brought Spain's worst political crisis in decades.
Separatist regional lawmakers made a unilateral declaration of independence on Oct. 27, prompting Spain's national government to take the dramatic step of firing the regional government and dissolving the Catalan parliament. Spanish Prime Minister Mariano Rajoy called an early election, which he is hoping will keep the separatists out of power.
The strategy could backfire, however, if the election delivers a pro-independence majority of lawmakers in the Catalan parliament. Even so, Rajoy says Catalan independence would go against the Spanish Constitution and he refuses to accept the possibility. The separatists, including a fugitive former leader evading Spanish authorities in Brussels and another campaigning from a jail near Madrid, are equally uncompromising.
A Catalan attempt to secede would be an unwelcome development for the European Union, which is already wrestling with legal complications from Britain's planned exit from the bloc. Senior EU officials have backed Rajoy, and no EU country has offered support for the separatists.
Catalonia's independence ambitions also have scant support in the rest of Spain.
Hatton contributed from Lisbon, Portugal.