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Cassandra Waldon, the very first "Big Brother" contestant to enter the house on the U.S. version, has died.

Cassandra passed away on September 25 ... apparently from injuries related to a car accident in Rome. A source at the United Nations -- where Cassandra worked -- tells TMZ ... she was struck by a car about 2 months ago, and suffered a head injury. We're told she never regained consciousness before her death.

Julie Chen, the host of "Big Brother," remembered Cassandra as a standout houseguest from the debut season in July 2000. Julie posted on Instagram, "Thank you for bringing your intelligence, warmth and wisdom to the Big Brother house Season 1."

She is the answer to the trivia question -- who was first to walk into the 'BB' house? That's kind of a double-edged sword ... as some fan blogs also point out she was first to fall victim to the so-called "First to Enter Curse."

No one who's entered first -- on the U.S. or Canadian (non-'Celebrity') versions -- has ever won the competition. Cassandra finished 6th out of 10 houseguests.

Cassandra worked at the UN as its Director of Communications for the International Fund for Agricultural Development. She was living and working in Rome when the accident happened.

We're told her funeral will be held next weekend in her home state of Maryland. Cassandra was 56.