Many OM646 owners do not know that this engine has a timing belt, not a timing chain. The belt drives not only the camshaft but also the injection pump, and the water pump runs off it as well. It is an interference engine: if the belt snaps, the valves and the pistons meet, and the end of it is a four-figure repair or an economic write-off. The factory replacement interval is 200,000 km or 10 years, whichever comes first. Experienced workshops shorten this to 150,000 km, especially on a car with an unknown service history or one that does a lot of city driving. At the change it is worth replacing the tensioner and the idler pulley as well, because their condition cannot be seen by looking, and the water pump too, since the same belt drives it. The complete change is 500 to 900 euro at an independent workshop and 800 to 1,400 euro at a franchised one. This is the most important preventive job on this engine.

The electrohydraulic brake system of the early W211 E-Class (and the related C219 CLS), the SBC, can switch into hydraulic backup mode because of software and hardware faults, with a longer pedal travel and more effort needed. The maker started several recalls (NHTSA 05V133 and its predecessors); the 2006 W211 facelift already got conventional hydraulic brakes, and the SBC was dropped because of complaints.

In the Mercedes 7 speed 722.9 automatic (7G-Tronic / 7G-Tronic Plus) the mechatronics unit and the conductor plate (Leiterplatte) age over time: jerking on shifts, delayed engagement, a "Getriebe schützen" message, and fault codes on the gearbox electronics.

The Mercedes Airmatic system holds the ride height with air springs and electronically controlled dampers. The most common faults over time are the relay, the compressor and a leaking air spring or air line.

The Mercedes 5 speed 722.6 automatic (5G-Tronic / NAG1) has three faults that also recur on the used market: (1) the control electronics sit inside the gearbox housing, and a leaking connector lets oil onto the electronics; (2) cooling faults around 2003 (and later) can let antifreeze into the ATF, which shortens its life; (3) wear of the torque converter lock-up clutch contaminates the valve body and causes jerky shifts.

According to the ADAC the W211 E-Class (2002 to 2009) has several faults that show up together.

The dual-mass flywheel is one of the most frequent expensive repairs on the OM646, especially on a manual car driven in town. Rivets hold the two discs together, and they can shear, which makes the flywheel run out of balance. It typically goes between 150,000 and 200,000 km, depending on driving style: a lot of setting off in town wears it sooner. The symptoms are vibration at idle and a metallic rattle when using the clutch. The imbalance can also ruin the clutch disc and the crankshaft sensor, so one flywheel fault turns into the replacement of several parts. The job is also expensive because the gearbox has to come out for it.

On this generation the injectors wear internally, and deposits build up on the nozzle needle from residual fuel and from the heat. A worn injector lets more fuel back into the return line than it should. The symptoms are rough running when cold, hard starting, sooting and a quiet knocking noise. The most reliable test is measuring the return quantity per injector. If the return of one injector stands out from the others, that injector is internally leaking. On the OM646 with the Bosch system the limit for the quantity correction is plus or minus 5 cubic millimetres per stroke: if an injector reaches that, it has to be replaced. This measurement says which unit is at fault faster than any fault code reading. The fault comes up above 180,000 km.