What single cause was responsible for the death of so many jamestown settlers in the early years?

Famine

Explanation:

Most of the Jamestown colonists were skilled tradesmen with little agricultural skills. They had the idea of trading finished goods with the local native tribes in exchange for foods.

Unfortunately for them, this plain failed because by the time, the tidewater area was going through a severe drought. This not only made farming harder for the colonists, but impeded trade because the native tribes did not had a lot of surplus food to exchange.

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