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It involved a red Ford Transit flatbed lorry which was travelling towards Westmorland Street, and a dark grey Peugeot 3008 which was travelling in the opposite direction. The vehicles collided head-on.
The 49-year-old male driver of the lorry, from Wetherby, was taken to Harrogate District Hospital, where he is in a serious but stable condition.
The 60-year-old male driver of the Peugeot, from Harrogate, was also taken to Harrogate District Hospital with slight injuries.
Police are investigating the collision, including the possibility that the lorry driver may have suffered a medical episode at the wheel, immediately prior to it.
Anybody who witnessed the collision, or either vehicle involved prior to it, is asked to contact North Yorkshire Police. Please call 101 and quote reference 12180188471.