Boys with a combination of depressive symptoms and raised levels of the stress hormone cortisol were up to 14 times more likely to be affected than those with neither trait, scientists found.
The diagnostic marker could help individuals most at risk of serious depression to get earlier treatment, the researchers believe.
"Depression is a terrible illness that will affect as many as 10 million people in the UK at some point in their lives," said study leader Professor Ian Goodyer, from Cambridge University.
"Through our research, we now have a very real way of identifying those teenage boys most likely to develop clinical depression.."
The scientists measured cortisol levels in the saliva of almost 2000 young people aged 12 to 19 and studied self-reported data about experiences of depression.
Rates of clinical depression and other psychiatric disorders in the group were recorded between 12 months and three years later.
Boys with raised levels of cortisol in the morning and pronounced symptoms of depression were 14 times more likely to develop serious depressive illness than those with normal cortisol and few symptoms.
The findings appear in the journal Proceedings of the National Academies of Sciences.