After nine years, Big Boss wakes up from the coma. He now has a prosthetic arm and a metal fragment in his head.
XOF, lead by Skull Face get to know that Big Boss is held in the hospital in Cyprus. Their goal is to eliminate Big Boss and every trace of their involvement. Quiet(girl) is sent to execute Big Boss.
While Quiet tries to strangle Big Boss, she is interrupted by another patient called Ishmael, who eventually sets her on fire. Quiet, burst into flames, falls out of the window.
With the help of Ishmael and Ocelot, he managed to get out of there and plan to rebuild mother bases called Diamond Dogs
Quiet undergoes medical parasite-treatment which allow her to stay alive and develop the ability to breath through her skin.
Big Boss aka Venom Snake finds and rescues Miller( leader of previous team), who has been kept captive in a Soviet outpost.
Venom Snake is sent in mission to find Quiet. He captures her and bring her to Mother Base, where she is held prisoner.
Venom Snake finds and rescues Huey Emmerich, but they are attacked by Metal Gear which is being controlled by Tretij. Venom Snake eventually destroys parts of the Metal Gear and manages to retreat to Mother Base.
In the meantime Quiet starts helping Venom Snake during various missions, and the two seem to create a bond.
Venom Snake finds Liquid Snake (known as Eli), a leader of a children soldier group. Eli is brought to Mother Base. Eli is extremely angry at his dad (Venom Snake) to the point he tries to kill him.
Venom Snake and Ocelot schedule DNA tests to see if Eli is his son. The tests are negative.
A tremendous epidemic spreads throughout Mother Base causing many members of the staff to die. To find a cure, Venom Snake goes on a mission to find Code Talker, who has been used by Skull Face to develop the vocal cord parasite. The parasite is said to infect only adult hosts who speak a specific language.(English)
Venom Snake finds and rescues Code Talker, who gives him the Wolbachia bacteria, the cure to the epidemic. Code Talker believes Skull Face intention is to use the parasite to wipe out all languages except for English as an ethnic cleanser.
Skull Face reveals that he have the same as Big Boss's vision of the world, and he wants to achieve this by silencing the world. He actually wants to use the vocal cord parasite to infect whoever in the world speaks English.
Venom Snake and Miller find Skull Face stuck under debris. Here they take their revenge for what he did to Militaires Sans Frontieres and Mother Base, by shooting him with his own gun and detaching his left leg and right arm. Huey Emmerich eventually shoots him in the head.
After Skull Face's defeat, a mutated version of the parasite gets loose in Mother Base, and Snake is forced to kill many of his own men. Quiet, who is recruited by Snake, saves his life, then goes into the desert to die. Huey is exiled. Confronting and embracing his dark side, Venom Snake prepares to found Outer Heaven, leading to the events of the original Metal Gear.
