The Syndicate had been operating for about 50 years before the threat of a rebellion of Faceless aliens was unearthed. This rebel group was focused on stopping the colonization of Earth and other planets. In 1998, they took part in the assassination of alien abductees at multiple sites, including one in Kazakhstan, Skyland Mountain, and a dam in Pennsylvania. At each location alien abductees had been drawn to the spots via a Metallic tag in each of the abductees' necks. The victims were then slaghtered by the Faceless Aliens using a flame weapon.
In 1999, the alien rebels attacked a train car outside of Washington, D.C., killing multiple Syndicate doctors who were operating on Cassandra Spender; however, they chose to let Cassandra live in hopes that she would expose the project. A rebel then proceeded to kill the Second Elder and took his identity in order to infiltrate the group. When he suggested that the Syndicate side with the rebellion, the Cigarette Smoking Man realized a rebel had infiltrated the group. He then sent Jeffrey Spender to kill him, although Alex Krycek would finish the job.
Shortly after this incident, a Syndicate surgeon attempting to remove the Alien fetus was killed by a Faceless Alien masquerading as a nurse. The rebel then took the fetus and disguised himself as the surgeon. He then proceeded with the medical team carrying Cassandra Spender to El Rico Air Force Base.
The Syndicate arrived at El Rico Air Force Base, in a party consisting of:
- The First Elder
- The Third Elder
- Cassandra Spender
- The Cigarette Smoking Man
- Diana Fowley
- The Fourth Elder
- The Fifth Elder
- Multiple other unknown associates.
The objective had been to deliver Cassandra Spender, the only known Hybrid, to the aliens, so that colonization could begin. However, when the doors opened and the Faceless Aliens barged in, the Syndicate members knew something was wrong. The Cigarette Smoking Man and Agent Fowley realized something was wrong as well, and took off before the rebels could reach them. The intruders surrounded the rest of the Syndicate, ignited their flame weapons, and destroyed the Syndicate.