Pioneer brothers Jim and Joe Downs experience love and loss in the newly-settled Ohio Valley. Although each has his own reasons for settling in the west—one led by his ministry, the other searching for adventure—they are united in their desire to make new lives for themselves. But when Jim and Joe are caught up in the local Indian war, each must confront what he would do to save the life of his brother.

The second novel in Zane Grey's Ohio River Trilogy, Spirit of the Border is loosely based on the lives of Grey's ancestors, who were among the first settlers on the Ohio frontier. Spirit of the Border is preceded by Betty Zane, and is followed by The Last Trail.

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