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The same things which make any other vehicle overheat. Which could be a wide range of things... lack of coolant, burnt out coolant, bad water pump, blockage in the cooling system, coolant loss due to a bad gasket (head gasket or intake manifold gasket - both are problematic with the GM 90 degree engines, which includes your 4.3 LU3 V6), bent fins on the radiator preventing airflow through the fins, lack of pressure in the cooling system due to a leak or bad radiator cap... you really need an actual diagnostic to narrow down the cause.

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Q: What makes a 2000 Chevy blazer overheat?
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