But the latest theory suggests he was the victim of a plot by his wife, Roxane. She is said to have poisoned him with what was then a little-known toxin taken from the strychnine plant.
The disclosure will intrigue followers of a historical whodunnit which has fascinated scholars down the ages. It may also prompt more interest in Alexander, who is making something of a comeback in the form of two new Hollywood films. Oliver Stone's movie Alexander the Great, starring Colin Farrell and Sir Anthony Hopkins, is released next month. Another blockbuster - with the same title - by the Moulin Rouge director Baz Luhrmann and starring Leonardo DiCaprio, is expected out in 2006.
The jealous wife theory is being propounded by Graham Phillips, an author of popular history, who believes Alexander was murdered by Roxane in revenge for taking another wife or perhaps flaunting his homosexual lover, Hephaestion, who also died in mysterious circumstances.
He believes that both Hephaestion and Alexander suffered the classic symptoms of strychnine poisoning. Roxane was one of the few people who could have known about the deadly derivative of the strychnine plant Strychnos nux vomica.
What little is known about Alexander's sudden death starts in Babylon, the cultural capital of the ancient world, with a funeral feast held at the end of May in 323BC in honour of the late Hephaestion.
Roman historians, drawing on original accounts of the banquet, suggest that Alexander was gripped by pain before collapsing. "The initial symptoms were agitation, tremors, aching or stiffness in the neck, followed by a sudden, sharp pain in the area of the stomach," Mr Phillips says in his new book Alexander the Great: Murder in Babylon, published this week.
"He then collapsed and suffered excruciating agony wherever he was touched. Alexander also suffered from an intense thirst, fever and delirium, and, throughout the night, he experienced convulsions and hallucinations.
"In the final stages he could not talk, although he could still move his head and arms. Ultimately, his breathing became difficult and he fell into a coma and died."
Toxicologists at the University of California told Mr Phillips that the symptoms fit those of poisoning by strychnine, a toxin that interferes with the chemical transmitters of the nerves controlling the body's muscles.
Strychnine would have been unknown in the West at the time because it came from a plant that only grew in the Indus valley, where Alexander has visited two years previously, he said.
Roxane, who accompanied Alexander, took an interest in local customs and is said to have visited a sacred grove where small doses of strychnine could have been used by local priests to induce spiritual hallucinations.
"The one person who know about strychnine was Roxane. She was not only in India, she knew about local customs. I came to the conclusion that she could have killed him," he said.
Professor Robin Lane-Fox of Oxford University, who acted as the history consultant for Oliver Stone, is sceptical of claims of Roxane's guilt.
"If you were going to kill Alexander you would want to make sure he was killed on the spot. You wouldn't want to risk a slow death by poisoning which would alert his suspicions," Professor Lane-Fox said.
"We don't know what really killed him. Alexander had many old wounds, he travelled in marshes riddled with malaria, he drank all night. He simply might have had a seizure," he said.