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Jean-Claude Trichet added the break-up was "totally contrary to the new world" of large emerging economies, with single currencies and single markets.
Asked how Brexit would affect the other EU countries, he said: "It's very much a question of proportion."
The EU's economy is worth about £13tn, compared to the UK's £2tn.
Speaking to the Wake up to Money programme, he said: "If I take the EU as a whole and compare the GDP of the EU to the GDP of the UK, you see there's a small portion which is the UK."
He added: "It's normal that the European 27 are less impacted themselves than the UK by this event which has been entirely decided upon by the UK - when all the 27 wanted the UK to stay."
'New world'
The EU is the UK's biggest trading partner, accounting for nearly half of all exports in 2016, according to official figures.
Brexit supporters argue new, lucrative trade deals can be made with fast-growing emerging markets.
Mr Trichet suggested Brexit will also be detrimental to the EU at a time of economic growth elsewhere in the world, arguing that it should be avoided "for the sake of the UK in the very long run, and for the sake of our continent".
He said: "In a period when India, China, Brazil, Mexico, Indonesia, and all emerging economies are going very fast and are dwarfing Europe more and more, how can it be that we decide to separate ourselves, to split? It is totally contrary to the new world. [...]