Reports say the front of Grade II* listed Tapton House was targeted after a trespasser gained access to its grounds.
The house, built in the late 18th Century, is the former home of railway pioneer George Stephenson who leased the house from 1832 until his death in 1848.
It is currently empty and heritage experts say it is vital a new use is found soon for the historic property to prevent further anti-social behaviour.
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Ian Scott, a member of Chesterfield and District Civic Society, discovered the graffiti and says the boundary walls have also been defaced.
The society’s chairman, Philip Riden, said: “This activity is objectionable in any context and especially so in the case of a Grade II* listed building with exceptionally fine brickwork.
"We have written to Chesterfield Borough Council asking them to extend the wire-mesh fencing currently erected around the main entrance to the whole building, so as to keep all but the most determined vandals at least two metres away from the ground floor walls and windows.
"If anyone succeeded in breaking into the property the consequences could be disastrous for one of the most important listed buildings in Chesterfield.”
Mr Riden said it was important the council acted quickly to clean up the graffiti and also find a long-term solution for the building.
“We hope also that the council will take immediate steps to remove the paint, so as to discourage imitation and if possible avoid permanent damage to the fabric,” he added.
"This may not be an easy or cheap task, given the nature of the brickwork, and may require listed building consent.
“Incidents of this sort emphasise that a long-term future must be found for Tapton House as soon as possible, preferably one that involves the building once again being occupied.”
Di Treece, co-chair of Friends Of Tapton House, told us last year that she wanted to see the building in use ‘for the education and enjoyment of the people of Chesterfield’.
“What we envisage is a cafe and some of the 17 workable rooms being let for courses and conferences, activities for schoolchildren or arts and crafts people,” she said.
We have asked Chesterfield Borough Council for comment.