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On April 1, 2020, Gaines signed a one-year contract to return to the Bills.

On March 25, 2019, Gaines signed a one-year contract with the Buffalo Bills. He was placed on injured reserve on August 10, 2019 with a core muscle injury. He was released on August 18.

Gaines signed with the Cleveland Browns on March 23, 2018, reuniting with former Rams defensive coordinator Gregg Williams. In Week 4 against the Oakland Raiders, Gaines intercepted quarterback Derek Carr and made five tackles in a 45-42 overtime loss. On November 7, 2018, Gaines was placed on injured reserve after being diagnosed with his second concussion in three weeks.

On August 11, 2017, the Los Angeles Rams traded Gaines and their second round pick (56th overall) in the 2018 NFL Draft to the Buffalo Bills in exchange for wide receiver Sammy Watkins and a sixth round pick (195th overall) in the 2018 NFL Draft. He started 11 games in 2017, recording 59 tackles, nine passes defensed, three forced fumbles, and one interception.

Gaines returned to the starting lineup in 2016, playing in 11 games with 10 starts, recording 56 tackles and seven passes defensed. He missed five games in 2016 due to a thigh injury.

Gaines brought forth his first child, Edwin “Tre” Gaines III, with Juanita Clare on January 23, 2016. The couple welcomed their second child Juliana Gaines July 8, 2018 and their third Ellius Gaines December 15,2019.

After earning the starting cornerback job the previous season and during training camp, Gaines was placed on injured reserve on August 15, 2015 due to a Lisfranc injury, ending his season before it started.

The St. Louis Rams selected Gaines in the sixth round (188th overall) of the 2014 NFL Draft. Gaines was the 25th cornerback drafted in 2014.

On June 23, 2014, the St. Louis Rams signed Gaines to a four-year, $2.32 million contract that includes a signing bonus of $107,672.

He started 15 games his rookie season in 2014, recording 70 tackles, 14 passes defensed and two interceptions, earning him a spot on the PFWA All-Rookie Team.

Considered a three-star recruit by 247Sports.com, Gaines was listed as the No. 44 cornerback in the nation in 2010.

In 2010, as a true freshman at Missouri, Gaines appeared in all 13 games recording 26 tackles, as a backup cornerback. In 2011, he won a starting position and set a school record with 18 passes defended, while also finishing the season fifth on the team with 69 tackles, and two interceptions. He earned first team All-Big 12 honors. In 2012, he led the team with 11 pass break ups and finished with a career-high 74 tackles. He also forced two fumbles and had an interception. In his senior season, he intercepted a career-high five passes while adding 75 tackles, earning himself a first-team All-SEC selection.

Gaines attended Fort Osage High School in Independence, Missouri. He was a two-time First-team all-state performer, and helped lead his team to the Missouri Class 5 title game as a senior in 2009, in which he ran for 1,500 yards and 20 touchdowns and caught 20 passes for 400 yards, while also starring in the secondary by making 72 tackles and two interceptions. His junior year, he had 89 tackles and added 5 interceptions (including one he returned for a score) in 2008. He recorded 88 tackles and five interceptions as a sophomore in 2007. He was also a standout performer in track and basketball for his school, as he won all-state honors in track two different years.

Edwin "E. J." Gaines Jr. (born February 23, 1992) is an American football cornerback for the Buffalo Bills of the National Football League (NFL). He played college football at Missouri. He was drafted by the St. Louis Rams in the sixth round of the 2014 NFL Draft.