Tony Nicklinson, 58, from Melksham, Wiltshire, communicates by blinking and has described his life as a "living nightmare" since a stroke in 2005.
Mr Nicklinson said he would appeal against the decision.
The case went further than previous challenges to the law in England and Wales on assisted suicide and murder.
Another man, known only as Martin, who is 47, also lost his case to end his life with medical help.
Father-of-two Mr Nicklinson was left paralysed with locked-in syndrome after a catastrophic stroke while on a business trip to Athens.
"Although I didn't want to raise my hopes, it happened anyway because a fantastic amount of work went into my case and I thought that if the court saw me as I am, utterly miserable with my life, powerless to do anything about it because of my disability then the judges would accept my reasoning that I do not want to carry on and should be able to have a dignified death.
"I am saddened that the law wants to condemn me to a life of increasing indignity and misery."
Explaining the decision, Lord Justice Toulson, said both cases were "deeply moving".
However he added: "A decision to allow their claims would have consequences far beyond the present cases. To do as Tony wants, the court would be making a major change in the law.
"It is not for the court to decide whether the law about assisted dying should be changed and, if so, what safeguards should be put in place.
"Under our system of government these are matters for Parliament to decide."
The case differed from other "right-to-die" cases which have focused on assisted suicide. Mr Nicklinson would be unable to take lethal drugs, even if they were prepared by someone else.
For someone else to kill him would amount to murder.
The rulings were welcomed by the group SPUC Pro-Life. Paul Tully from the organisation said: "Compassion and solidarity are the humane and caring responses to locked-in syndrome. To legalise killing of those who are suffering would adversely affect many, many people.
"We trust that today's judgment will help end the insidious campaign in the British courts to change the law on assisted suicide and euthanasia."
The British Medical Association said the court had made "the right decision".
Dr Tony Calland, from the BMA's medical ethics committee, said "The BMA does not believe that it would be in society's best interests for doctors to be able to legally end a patient's life.
"The BMA is opposed to the legalisation of assisted dying and we are not lobbying for any change in the law in the UK".
During the hearing in June David Perry QC, who is representing the Ministry of Justice, said Mr Nicklinson's "tragic and very distressing circumstances evoke the deepest sympathy".
"Notwithstanding the distressing facts of his situation, the defendant submits that the claim for declarations is untenable. The law is well established," he added.
The case was contested on the issue of "necessity" arguing that the only way to end Mr Nicklinson's suffering is to allow him to die.
This was used in 2000 when conjoined twins were separated, saving one even though doctors knew the other would die.
Mr Nicklinson's team also argued that his case is covered by Article Eight of the European Convention on Human Rights which deals with the right to respect for private and family life.
OP: This is nothing short of heartbreaking. The pro-lifers can say what they like but they're not actually suffering it are they? He's had practically everything else taken from him, so why not afford him his choice.