Fire officials said the large fire broke out just before 7 p.m. at the Inn at the Waterpark on Jones Drive, not far from Moody Gardens.
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The multi-alarm blaze caused the roof to collapse and left heavy fire damage on the second floor. No injuries were reported.
Firefighters said only two rooms had guests, and everyone was evacuated safely. It's unconfirmed how many rooms were damaged by the flames.
Several area fire departments reportedly assisted in battling the blaze.
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The hotel was said to have been in business for a number of years, and firefighters said it used to be a Howard Johnson's.
The cause of the fire is under investigation.