Pierson Prioleau's journey in professional football began when he was selected by the San Francisco 49ers in the fourth round of the 1999 NFL Draft. A safety by trade, Prioleau brought a solid defensive presence to the teams he played for throughout his career. His tenure with the 49ers marked the start of an 11-year career in the National Football League, where he became known for his reliability and work ethic on the field.

After spending two seasons with the 49ers, Prioleau moved on to the Buffalo Bills in 2001. During his time with the Bills, he continued to develop his skills as a defensive back, contributing to the team's secondary with his tackling ability and understanding of the game. His performance in Buffalo helped solidify his reputation as a dependable player in the league.

In 2005, Prioleau signed with the Washington Redskins, where he reunited with defensive coordinator Gregg Williams, under whom he had previously played in Buffalo. This reunion proved beneficial, as Prioleau became an integral part of the Redskins' defensive schemes. His time in Washington was marked by consistent play, although his 2006 season was cut short due to a knee injury sustained in the opening game.

Prioleau's career continued with the Jacksonville Jaguars in 2008, where he brought his veteran experience to the team's defense. His role with the Jaguars was primarily as a backup safety and special teams contributor, showcasing his adaptability and team-first mentality.

In 2009, Prioleau joined the New Orleans Saints, where he was part of the team that won Super Bowl XLIV. Although his role was not as a starter, his presence on special teams and as a backup safety provided depth to the Saints' roster. Winning the Super Bowl was a highlight of Prioleau's career, capping off his years in the league with a championship ring.

Prioleau's final season in the NFL was with the Saints in 2010.

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