Winfield entered training camp slated as a starting cornerback after Thomas Smith departed during free agency and signed with the Chicago Bears. Head coach Wade Phillips named Winfield and Ken Irvin the starting cornerbacks to begin the regular season. In Week 9, Winfield collected a season-high nine combined tackles during a 23–20 victory against the New York Jets. On November 5, 2000, Winfield sustained a shoulder injury during a 16–13 win at the New England Patriots. On November 19, 2000, Winfield further aggravated his shoulder injury during a 21–17 victory at the Kansas City Chiefs. On November 24, 2000, the Buffalo Bills placed Winfield on injured reserve after it was discovered he had a torn labrum cartilage in his right shoulder that would require surgery.