The Worcester Cold Storage and Warehouse Co. fire began on December 3, 1999, in a 93-year-old abandoned building at 266 Franklin Street, Worcester, Massachusetts. The fire was started accidentally some time between 4:30–5:45 pm by two homeless people (Thomas Levesque and Julie Ann Barnes) who were squatting in the building and had knocked over a candle. They left the scene without reporting the fire. The 6-story building, previously used as a meat cold storage facility, had no windows above the ground floor and no fire detection or suppression systems. The fire, which started on the second story, burned undetected for 30–90 minutes.

The structure was located five blocks east of the Worcester central business district, near Union Station and adjacent to Interstate 290. An off-duty police officer first called in the fire at 6:13 pm after noticing grey/white smoke coming from the roof of the building. At around the same time an off-duty firefighter from neighbouring Auburn passed the building on I-290 and radioed his Fire Control to report smoke coming from the roof. He told them to inform the Fire Chief "this is going to be a multiple-alarm fire."

Firefighters were unfamiliar with the layout of the building, and most of the floors inside — each up to 15,000 square feet (1,400 m²) — were divided into a labyrinth of connecting meat lockers. The walls and many ceilings were covered with insulating layers of cork, tar, expanded polystyrene foam, and spray-applicated polyurethane foam. There were no fire walls or fire doors, and only a single staircase extended from the basement to the roof.

The owner of a neighboring business informed a police officer at the scene that a homeless couple had been squatting in the building and firefighters initiated a search, believing they could still be trapped inside. Conditions inside the building deteriorated rapidly. Worcester Fire Department District Chief Michael McNamee said: "There was a light smoke condition in the upper levels of the building to the point we didn't even have our face pieces on. Within four seconds it went from that condition to the building being filled completely with black, hot, boiling smoke." The layout of the building and the absence of windows left firefighters without a secondary escape route and prevented ladder and rescue operations. Six firefighters were still unaccounted for in the building when the interior floors collapsed to the second story level. They were the city's first firefighting deaths in 36 years.