Together, the pro-independence Together for Catalonia, leftist ERC and radical left CUP parties were on course to take 70 seats — an absolute majority in a 135-seat parliament.
Those results at 2120 GMT were based on a count of just over 65 percent of the total number of votes. The final count, expected later Thursday, could still turn the trend.
Ciudadanos, a centrist party formed in 2006 to counter Catalan separatism, looked set to win its best ever result: 25 percent of votes and 35 seats.
But even if Ciudadanos goes into coalition with the remaining contenders, it is almost impossible for pro-unity parties to end up governing, except in one scenario: if the separatists fail to clinch a deal.
The Catalan vote, which saw an exceptionally high turnout, was called just two months after a failed secession bid triggered Spain's worst crisis in decades.
Catalans on both sides of the separatist divide saw the day as a nail-biting moment of truth, following weeks of upheaval and protests unseen since democracy was reinstated following the death in 1975 of dictator Francisco Franco.