2000 C280, 77K miles... running rough, engine obviously misfiring, check engine light illuminated. Decreased performance and increased fuel consumption was noted in the weeks prior to the CE light illuminated.

Initial fault code check revealed P0300 & P0302. Renewed cylinder # 2 ignition coil, with no change in performance. Rechecked codes: P0300, P0302, P0306 present; data stream revealed misfire rates of 57.88 for both cylinders. Replaced # 2 coil again with known good coil and renewed cylinder # 6 coil; renewed # 2's plugs and plug wires, also plugs for cylinders 1 & 3. Check engine light still illuminated; recheck revealed P0300 & P0302, with 57.88 for cylinder # 2.

Ran a can of LubroMoly fuel injector cleaner in case # 2 injector was fouled and rechecked codes: now cylinders 1, 3 & 4 show misfire codes, with rates approaching 57.88. Cylinder 2 now shows a misfire rate below threshold, but misfire event counter was twice observed to rapidly rise to 99 but then could not be repeated. Misfire event counter for other cylinders remained at 0. Problem intensity appears to be variable, since driveability can be poor at times and at other times normal.

Whats happening here? Should all coils be replaced or is something else responsible for this increasing rate of misfiring?

Not completely familiar with this engine but it sounds like you have a dirty fuel injector or possibly a heat related failure of the injector. I am guessing that the car has individual injectors for each cylinder. Individual coils for each cylinder with two spark plugs each cylinder. What I think is happening the injector is not closing off completely allowing fuel to leak by when the injector is closed. This will enrichen the mixture. If the leak is bad enough it will foul the spark plugs for that cylinder.
First pull one plug from each cylinder after the car misfires at idle for a couple of minutes. This will cause the problem to be seen as a dark spark plug center electrode. The center electrode from a good running cylinder will be white to a very light brown in color. If you see a dark plug pull the other spark plug from that cylinder to see if maybe the spark is not getting to both plugs. Look for one (or more than one) that is darker than the other plugs and there is you're problem. I would try to move the injector around to another cylinder and see if the problem follows the injector. If only one injector is running rich then you might be able to get away with one new injector and a new fuel filter. If more than one injector is bad replace the fuel filter and the injectors. New fuel filters are cheaper than fuel injection problems. Be sure to replace the fuel filter and run the car before replacing injectors. You do not want any prior problems getting into new parts.
If the problem stays with the one cylinder run a compression test to see if you have low compression on the problem cylinder. Probably not because the problem comes and goes away. Low compression problems will stay there.
If the car is running rich on one cylinder it tries to lean out the other cylinders to compensate for the rich cylinder. Causing other problems. Good luck finding the problem. John

P300 and 302.......aren't those related to plugs? I had the same misfire symptom in wet weather and my plugs were shot, resistor caps and wires were cracked as well. Replaced all, problem solved.

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former: 83 300D, 97 C230, 93 400E

current: 08 C300 Luxury , 92 500SL