Local authorities say 86 per cent of voters backed autonomy, an unsurprising figure since the president, Evo Morales, had declared the referendum "illegal" and urged citizens not to vote so as to deny it legitimacy.
Leaders in Santa Cruz want greater autonomy in order to keep more of the province's natural gas revenues and to protect their large plantations and ranches from Morales's plan for land redistribution.
But Morales claimed that as many as half the ballots on Sunday were invalid, quoting media reports.
"The referendum failed completely," he said in a nationally televised address.
But he ended his remarks with an invitation for more talks with autonomy leaders.
"Let's work together tomorrow for a true autonomy," he added. "For the people, and not just certain groups - an autonomy that permits the people to decide their destiny."
The president says he needs a strong central government to distribute Santa Cruz's wealth to the rest of the country.
The struggle between the country's rich against the socialist president and the poorer indigenous people has triggered sporadic fighting with as many as 25 people injured so far.
The situation has exposed the divide between the indigenous Indians, who make up 60 per cent of the population and largely live in the Andean mountains, and the better-off inhabitants of the lowlands, many of whom have European ancestors.
As poll stations opened on Sunday, several men clashed near a polling station in Plan 3000, a southern neighbourhood mainly populated by indigenous Indians, who are against autonomy.
|Violence between pro- and anti-autonomy |
supporters has left 25 people hurt [Reuters]
A crowd of indigenous Indians also attacked a polling station in Santa Juliana, a town lying 140km north of Santa Cruz city.
Al Jazeera's Newman said some of the clashes were serious and government supporters blocked roads in Santa Cruz to prevent people from reaching polling stations and burned ballot boxes.
Relatives of a 70-year-old man said he was killed when police fired tear gas to break up one scuffle, but the authorities could not confirm the death.
Morales congratulated protesters for trying to block the vote.
"I want to express my respect for the people of Santa Cruz for their resistance against this separatist referendum," Morales said. "The people are wise to defend legality, constitutionality and the struggle for equality between Bolivians."
Despite the violence, voter turnout was high.
Morales, the country's first indigenous president, has not followed through with a threat to bring troops into the region, but has said that he will ignore the result of the vote, calling the move unconstitutional and separatist.
"They're only in it for the money, not for the country. They're only in it to help out a few businessmen, and not the people," he said on Saturday.
He had earlier suggested that the dispute could be decided by a nationwide referendum.
However, he also said that some of the state's demands may be worked into Bolivia's new constitution if the referendum were approved.
No one is clear exactly how autonomy would alter Bolivia's heavily centralised government.
The statutes up for approval on Sunday would create local powers common in many countries, including a state legislature and police force.
Morales particularly objects to ambitious clauses that bear the distinct ring of nationhood: control of the state's land distribution and the right to sign international treaties, among others.
More to come
The vote went ahead despite an order to postpone it by Bolivia's top electoral court, and few international observers were present.
While the vote is not constitutional technically, it is democratic and therefore has a certain political legitimacy.
It is also just the beginning of a series of ballots on autonomy in Bolivian regions.
Three others provinces are to hold their own votes on autonomy next month, while two more are considering holding a referendum.