In the most complex scientific experiment ever undertaken, the Large Hadron Collider (LHC) on Wednesday will be switched on, accelerating sub-atomic particles to nearly the speed of light before smashing them together.
"The LHC will increase the energy at which we can study particle interactions by a factor of four. According to present thinking, this should be enough to discover the Higgs particle," Hawking told BBC radio.
"I think it will be much more exciting if we don't find the Higgs. That will show something is wrong, and we need to think again. I have a bet of $100 that we won't find the Higgs," added Hawking, whose books including A Brief History of Time have sought to popularise study of stellar physics.
On Wednesday the first protons will be injected into a 27km ring-shaped tunnel, straddling the Swiss-French border at the headquarters of the European Organisation for Nuclear Research (CERN).
Physicists have long puzzled over how particles acquire mass. In 1964, a British physicist, Peter Higgs, came up with this idea: there must exist a background field that would act rather like treacle.
Particles passing through it would acquire mass by being dragged through a mediator, which theoreticians dubbed the Higgs Boson.
The standard quip about the Higgs is that it is the "God Particle" - it is everywhere but remains frustratingly elusive.
While questioning the likelihood of finding Higgs Bosons, Hawking said the experiment could discover superpartners, particles that would be "supersymmetric partners" to particles already known about.
"Their existence would be a key confirmation of string theory, and they could make up the mysterious dark matter that holds galaxies together," he told the BBC.
"Whatever the LHC finds, or fails to find, the results will tell us a lot about the structure of the universe," he added.
Hawking, the 66-year-old Lucasian Professor of Mathematics at Cambridge University, was diagnosed with the muscle-wasting motor neuron disease at the age of 22.
He is in a wheelchair and speaks with the aid of a computer and voice synthesiser.