The highway is now closed between Hospital Rock and Giant Forest near the southern entrance to the park.
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Officials say drains on the highway were damaged by severe flooding.
With the closure in place, visitors won't be able to reach the giant sequoias by using the park entrance in Three Rivers.
This is the second time Generals Highway has been shut down in the past couple of weeks.
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Rock and mudslides forced the highway to be closed on New Year's Day.
Stay with Action News for updates on this developing story.