thumb|220px|Bills RB C. J. Spiller rushing against the Patriots in 2013 The rivalry with the New England Patriots began when both teams were original franchises in the American Football League (AFL) prior to the NFL–AFL merger, but did not gain notability until the emergence of New England quarterback Tom Brady in 2001. The teams were very competitive prior to the 2000s. However, Brady's arrival in the early 2000s led to the Patriots dominating the AFC East, including the Bills, for two decades. As a result, New England replaced the Dolphins as Buffalo's most hated rival. The Bills have taken a 8–3 edge since Brady's departure in 2020, which included consecutive AFC East titles from 2020 to 2022 and a season sweep of the Patriots in two of the three years. In 2021, the Bills dominated in a 47–17 victory against the Patriots in the two teams' first playoff match-up in 59 years, which saw the Bills score a touchdown on every offensive drive throughout the entire game and, as such, is the only "perfect offensive game" in NFL history. Overall, the Patriots lead the series 79–51–1 as of 2024, but trail the Bills by a 48–47–1 margin without Brady on the field.
thumb|220px|Bills RB C. J. Spiller rushing against the Patriots in 2013 The rivalry with the New England Patriots began when both teams were original franchises in the American Football League (AFL) prior to the NFL–AFL merger, but did not gain notability until the emergence of New England quarterback Tom Brady in 2001. The teams were very competitive prior to the 2000s. However, Brady's arrival in the early 2000s led to the Patriots dominating the AFC East, including the Bills, for two decades. As a result, New England replaced the Dolphins as Buffalo's most hated rival. The Bills have taken a 8–3 edge since Brady's departure in 2020, which included consecutive AFC East titles from 2020 to 2022 and a season sweep of the Patriots in two of the three years. In 2021, the Bills dominated in a 47–17 victory against the Patriots in the two teams' first playoff match-up in 59 years, which saw the Bills score a touchdown on every offensive drive throughout the entire game and, as such, is the only "perfect offensive game" in NFL history. Overall, the Patriots lead the series 79–51–1 as of 2024, but trail the Bills by a 48–47–1 margin without Brady on the field