A man and a woman died from their injuries, ABC News affiliate KBMT-TV reported. Their names were not immediately available.
The DPS said it won't know the exact number of cars involved in the pileup until officials finish untangling the wrecks.
At least five people who were taken to the hospital are in critical condition, KBMT reported.
The accident happened in Jefferson County shortly after 8 a.m. Thanksgiving morning on Interstate 10 between Taylor Bayou and Hampshire Road.
Fog blinded drivers, with investigators saying most couldn't see a foot in front of them at the time of the crash.
"The cause of the accident was a heavy fog bank rolled into this area this morning, which caused nobody to be able to see and caused one accident that triggered another accident and then a chain reaction," said Deputy Rod Carroll of the Jefferson County Sheriff's Department.
"Even as the deputies were pulling up we still had a continuous chain of accidents," Carroll said.
An 18-wheeler tanker truck began leaking after the chain-reaction accident, KBMT reported.
The eastbound side of the freeway was closed for hours and remained closed into the afternoon, DPS told ABC News. The westbound lanes opened shortly after noon