The accident happened just before 12:30 p.m. in the westbound lanes of I-84 near exit 5 in Montgomery.
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Authorities say two tractor trailers and four cars were involved, and that two patients were airlifted to an area hospital.
PHOTOS: I-84 crash in Orange County
The exact number of injured is unknown, but police have confirmed at least one fatality. Another victim had to be extracted from one of the vehicles.
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The cause of the accident is under investigation, but it is believed that speed was a factor as one of the trucks entered a construction zone where the lanes narrowed from four to two. The impact pushed two vehicles underneath the second tractor-trailer.
All lanes have since reopened to traffic.
The crash happened just a few miles east of where a multiple-vehicle crash shut down I-84's westbound lanes for four hours Monday.