Pennsylvania suffers an outbreak of "Green Flu"; a highly contagious virus causing extreme aggression, mutation to the body cells, and loss of higher brain functions.
Two weeks after the infection four immune survivors— Bill, a Vietnam veteran; Zoey, a college student; Louis, an IT analyst, and Francis, an outlaw biker — make their way through the city of Fairfield, only to discover that the virus is creating more dangerous mutations .
After narrowly avoiding these new infected, along with hordes of others, the survivors are alerted to the presence of an evacuation point at the nearby Mercy Hospital roof by a passing helicopter .
Fighting their way through the city's streets, subway and sewers, they are rescued from the hospital's roof by the pilot, only to discover he is infected ("No Mercy").
With Zoey forced to kill the pilot, the helicopter crash lands in an industrial district outside the city.
Finding an armored delivery truck, the group uses it to make their way to the town of Riverside ("Crash Course").
However, they find the road blocked, and travel the rest of the way on foot. After an encounter with an infected lunatic in the local church, they discover that the town is overrun, and decide to head to a nearby boathouse for rescue.
Contacting a small fishing vessel, they manage to reach the city of Newburg on the other side of the river, only to find much of it in flames ("Death Toll").
Seeking cover in a large greenhouse , their rest is interrupted when a military C-130 Hercules passes overhead, leading the survivors to travel through the city's business district towards Metro International Airport.
Upon arrival, the group see that in an attempt to contain the infection, the military had bombed the airport while infected pilots crash planes in an attempt to land; the runway however is largely intact, allowing the survivors to fuel up and escape in a waiting C-130 ("Dead Air").
Despite this apparent rescue, it crashes as well, and the survivors once again find themselves alone on the outskirts of Allegheny National Forest .
Following a series of train tracks through the area, the group find themselves at a functioning, but abandoned, military outpost.
After answering a radio transmission, the survivors make their final stand against hordes of infected, before a military APC arrives to transport them to Northeast Safe Zone Echo, supposedly the only uninfected area yet to be overrun ("Blood Harvest").
Instead they are kept at a military installation and informed that even though they are immune, they still carry the virus .
They are temporarily held by the military before the base is overrun with infected.
The four escape via train and travel south at Bill's insistence; Bill believes that they can find long-term safety from the infected on the islands of the Florida Keys ("The Sacrifice comic").
At the portside town of Rayford, they find a boat but must raise an old rusty bridge powered by an aging generator to get the boat into open waters, assured that the machinery noise will alert a large horde.
When Louis is injured and unable to move quickly, Bill sacrifices himself against the horde to make sure the generator keeps running and allowing the three to stay clear of the horde. ("The Sacrifice")
After waiting for the horde to disperse, the three remaining survivors are taking time to mourn Bill's death when they encounter the four survivors from Left 4 Dead 2 , who need to cross the bridge to continue to the west ("The Passing").
Zoey, Louis, and Francis help the four to get across and fend off another horde as they lower the bridge, and then set sail for the Keys.