Morales told The Associated Press on Friday that he would meet autonomy demands with "patience" and would consider working Santa Cruz's wishes into his proposed constitution.
Santa Cruz Gov. Ruben Costas emphasized that Sunday's referendum is but one step. Three more eastern lowland states — Beni, Pando, and Tarija — hold autonomy votes in June, and two other states are considering similar referendums.
"This process does not begin or end on May 4," Costas said at a news conference Saturday. "Nobody should be frustrated if we don't wake up on Monday totally autonomous."
No one is clear what autonomy would look like, but the ambitious statutes up for approval Sunday would create local powers apart from the central government, such as a state legislature and police force.
Santa Cruz leaders insist that they have no intention of seceding — an unlikely prospect for a right-wing state wedged between Morales' leftist allies in Brazil and Argentina.
But Morales takes particular issue with the few clauses that bear the distinct ring of nationhood: complete control over land distribution and the right to sign international treaties, among others.
Support for any form of local rule runs high in the state's namesake capital. Pro-autonomy graffiti fights for space on the city's walls, and Santa Cruz's green-and-white flag flutters from cars and shop windows all over town.
Local polls showed the referendum drawing as much as 70 percent support going into election day.
Long isolated from Bolivia's high-altitude capital of La Paz, rural Santa Cruz has aspired to greater self-rule for generations, and movement has caught fire since Morales' 2005 election as Bolivia's first indigenous president.
But some say autonomy is just one more turn of the tide in Bolivia's long unstable history, unlikely to change many Bolivian lives.
"So the Santa Cruz teachers start receiving their salaries from the state instead of the national government," said Fernando Molina, editor of the news weekly Pulso. "They'll be the same teachers we have now, and the students will have the same deficiencies we have now."