Firefighters have found at least 19 bodies with at least 25 people being treated for injuries.
The blaze engulfed an orphanage for abused children near Guatemala City just one day after a riot broke out at the centre.
Firefighters said at least nine children died from burns after becoming trapped in the fire in the Virgen de Asuncion shelter in San Jose Pinula.
At least 25 people were injured and transferred to hospitals and we have confirmed 19 bodies
Guatemala’s volunteer fire department spokesman Mario Cruz told the Emisoras Unidas radio station firefighters were still extinguishing parts of the fire.
Oscar Franco, a spokesman for the volunteer firefighters, told local media: "At least 25 people were injured and transferred to hospitals and we have confirmed 19 bodies."
Police said burning mattresses caused the fire with an investigation launched into the inferno.
At least 19 people have been killed in a fire at a Guatemala orphanage
At least 25 people were injured in the fire
Victims were rushed to nearby hospitals
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Crowds of people surround the children's home
The police officer said: "We are now going to evacuate the rest of the children to protect their lives.
"We know that the fire started with mattresses, it is unknown in what area they began and in due course we will give more information.”
It is thought some 540 children live at the orphanage, despite its capacity to hold only 400.
Worried families gathered outside the care home as riot police stand guard.
The Virgen de Asuncion home is in the municipality of San Jose Pinula, some 25 kilometres south west of the capital Guatemala City and houses children of up to 18 years old.
Concerned relatives wait outside the home for updates
Local media said 540 children live in the home
Riot police stand guard outside the Virgen de Asuncion shelter
Police confirmed other youngsters were being taken to safety.
The blaze comes just one day after a riot broke out at the home.
Police were called on Tuesday after around 60 children escaped claiming they had been mistreated of sexually abused.
Local media claim the children’s home has also been functioning as a juvenile detention centre.
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