Babies born with faults in three key lung genes have 14 times the risk of dying from cot death, researchers say.
Putting a baby to sleep on its back reduces the risk of cot death
All the genes, identified by a team from Manchester University, play a part in the body's immune system.
The researchers say the work, published in New Scientist and Human Immunology, could help identify babies at risk, so they could be closely monitored.
Campaigners welcomed the study, but said cot death was still the main cause of death in babies.
Cot death, also known as SIDS or sudden infant death syndrome, killed 329 babies aged between one month and two years in England and Wales in 2004.
However, rates have been falling since the campaign to place a baby to sleep on its back was launched in 1991.
The Manchester team had previously found there was a link between increased cot death risk and specific variants of a gene called Interleukin 10 (IL-10).
In this study they discovered two further immune system genes - Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) - which also increase a baby's risk.
All three genes are involved in the production of chemicals called cytokines which play a key role in ensuring the immune system operates as it should.
The researchers say specific variants of the Interleukin genes mean a baby's immune system goes into overdrive when it encounters a bacterial infection - resulting in cot death.
In the case of VEGF, the variant which is linked to SIDS could also result in poor foetal lung development.
This combination appears to be particular dangerous for babies.
The idea that cot death is linked to flaws in the immune system genes is supported by other studies which linked the condition to common bacteria to which babies may lack immunity.
Infants aged between two and four months in particular have a very weak immune system.
If other known risk factors are present - such as being exposed to cigarette smoke or being placed in the "wrong" position in their cot - a baby's risk becomes greater, the researchers said.
Breastfeeding has been suggested to offer babies protection against infection.
'Miscarriages of justice'
Dr David Drucker, who led the study, said: "This research greatly advances our understanding of the basic causes of SIDS, which is not a single disease but a collection of different causes of death.
"Being able to detect high-risk babies means that health care and social provision can be aimed at the most vulnerable infants.
"In theory, commercially available and licensed human immune serum could be given to those children most at risk."
Dr Drucker, whose has also examined why smoking and sleeping position are risk factors for SIDS, says this latest research will help establish the cause of death in certain cases.
"Forensic scientists would be able to assess the likelihood of a baby dying from SIDS through genetic measurements and so help prevent the sort of tragic miscarriages of justice that have happened in the past."
A spokesman for the Foundation for the Study of Infant Deaths said: "Sudden unexpected death remains the greatest hazard for infants in this country after the neonatal period.
"The mechanism has always been thought to include a vulnerability of individual babies at around two to three months of age.
"We know predisposing factors to this vulnerability such as prematurity, low birth weight, and exposure to cigarette smoke before and after birth.
"And we know of factors in the infants' environment or care such as sleeping on their front or in bedding designed for adults, or overheating, which increase risks."
"Parents and professionals want more work into the factors which make babies vulnerable."