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Winn-Dixie was a long-time grocery chain in several locations in Clemson. The original store was located at the south end of College Avenue where Mr. Knickerbocker is now in business. The second store opened in December 1960 at the bottom of the hill below downtown in the location now occupied by the Blue Heron and other businesses. This store closed in the summer of 1975 with the construction of a new larger facility on the US 123 By-pass (now Tiger Boulevard) in Lakeview Plaza. Winn-Dixie would move again to another new facility on the east side of the Old Greenville Highway (SC 93).

With the financial difficulties experienced by the chain in 2003 which would culminate in a bankruptcy filing on February 22, 2005, the chain announced in April 2004 that it would close 156 stores, including all those in North and South Carolina. This marked the departure from Clemson of one of the grand old names of retailing in the Clemson community.

Bi-Lo would later buy the vacated store across SC 93 from its Clemson store to prevent competition from moving into the old Winn-Dixie.