Some problems with the 6.6 Duramex include water pump failure, overheating, injector failure, glow plug failure and turbocharger oil ingestion. Other issues include injector harness chafing and fuel starvation or air in the fuel lines.
It is common that a water pump require replacement within the 80,000 to 100,00 mile range because of failure caused by the factory water pump design. Overheating issues are less common with the 6.6 Duramex, and General Motors corrected the premature injector failure in designs later than the 2004 model year. Because the Duramax does not use a lift pump and due to the fuel fitter housing design, it is susceptible to fuel starvation and air in the fuel lines.