Adobe Books at 16th and Valencia has been evicted to bring in Jack Spade, a luxury men's brand owned by Liz Claiborne.
The Mission Merchant's Association has started posting signs, saying they support local business and oppose Jack Spade.
Customers told ABC7 News they want to keep the area's character intact.
"Rents are high enough around here," neighbor Michael Katz said. "If we have big chains coming in here, basically we're gonna be seeing one more neighborhood where small business are pushed out, chains come in and the special flavor, special identity of one more neighborhood in San Francisco will be compromised."
Zoning laws keep big chains from setting up shop in the area, though Jack Spade doesn't quite fall into that category with 14 stores.
Opponents have started a petition they hope will persuade Jack Spade not to open.
ABC7 News tried to contact the owners of Jack Spade, but was unsuccessful.