While hospital officials are hoping for the best, they said they are preparing for the worst when the I-405 closes from Friday night to Monday morning from the 101 to 10 freeways.
"We've actually staffed up a little bit in anticipation that something could go wrong where we would have to treat a big emergency," said Gary Bowman of Saint John's Health Center.
The hospital is also prepared in the unfortunate event that something goes wrong as crews work to rebuild the Mulholland Bridge.
"With the work going on on the freeway, that's definitely part of our consideration because there's the possibility of a major accident with the construction that we would have to be able to take care of," Bowman said.
Some staff members who would normally commute from the valley will be making the hospital home for the weekend.
"We've looked at trying to arrange staff who live on the west side of the I-405 or are local, so that we don't have to deal with commute issues or staff remaining overnight over the weekend," said Steven Sharrer, the vice-president of the hospital's human resources.
The emergency department will be fully operational during "Carmageddon 2," as will other departments. But a few adjustments have been made to the elective surgery schedule.
"We're trying to have local patients so that they don't have to deal with the commute and potential traffic areas," Sharrer said.
Hospital officials are hoping "Carmageddon: The Sequel" is as successful as the first production, and they said it will be if drivers heed the warnings and steer clear of the 405 Freeway this weekend.
Anyone in a life-threatening situation should still call 911.