Winfield made his professional regular season debut in the Buffalo Bills’ season-opener at the Indianapolis Colts and recorded three combined tackles and made his first career interception during their 31–14 loss. Winfield made his first career interception off a pass attempt by Colts’ quarterback Peyton Manning, that was originally intended for the wide receiver Jerome Pathon, and returned it for a three-yard gain in the fourth quarter. On December 26, 1999, Winfield earned his first career start in place of Ken Irvin who was placed on injured reserve due to a foot injury he sustained the previous week. He finished his first career start with one tackle during their 13–10 victory at the New England Patriots in a Week 16. In Week 17, Winfield collected a season-high 11 combined tackles as the Bills defeated the Indianapolis Colts 31–6. He finished his rookie season in 1999 with 40 combined tackles and two interceptions in 16 games and two starts.