Designer clothes outlet Harrison, on Ecclesall Road, is to shut on March 31 after 33 years in business.
The store has been targeted six times by criminals since December 8, with the most recent incident involving a vehicle driving through the front door shutters to gain entry.
Owner John Harrison says he had no choice but to bow out as his family could no longer deal with the financial loss and emotional turmoil.
John said burglaries had happened occasionally since the store first opened, but not to the extent seen in recent months.
He described a Boxing Day raid as the ‘final straw’ in what had been a stressful period for the family.
John, aged 61, said: "We hadn't been trading much in the lead-up to Christmas, so we'd lost a fortune as it was. This added to our losses and was distressing for the family.
"You can't help but take these problems home with you. It ruined our Christmas."
John admitted he knew little about running a clothes shop when Harrison opened its doors in 1986.
He started in the trade by buying clothes from contacts in London and driving them up to Sheffield in the boot of his car.
It has been onwards and upwards ever since for Harrison, which has steadily become one of the most popular independent clothes stores in the city, stocking expensive luxury brands like Barbour, Paul Smith, Hackett and Hugo Boss.
Security measures have been put in place to protect the premises from thieves but the groups targeting the place are ‘relentless’, John said.
‘’Occasional break-ins are expected with the clothes we sell but we’ve never had it like this before,” he added.
John now lives in North Yorkshire. He will be putting the shop on the market next week but insists he will only offer a lease, or sell, to a company that reflects the values established by Harrison.
The shop's Facebook post announcing its upcoming closure received over 1,000 shares and hundreds of supportive comments.
John paid tribute to the loyal customers who had helped the business achieve success.
He said: "I will miss the banter more than anything else. We are one of the few local businesses that do what we do – it's all the big boys now. The business is something I've built. It's more than just a shop, it's my life."
Despite the store's closure, John's life in Sheffield is far from over as he will continue visiting the friends he has made over the years, allowing memories of Harrison to live on.
John said: "I left school at 15 and haven't stopped since, so stopping is quite frightening. Luckily I have a big family which will keep me occupied and happy."