One problem related to transmission failure has been reported for the 2000 Ford F-450. The most recently reported issues are listed below.
Transmission failure of 4r100 Ford transmission that has been serviced by Ford since 2000 (when bought) and no mention of a factory overheating problem that an upgraded cooler (per TSB) would have avoided.
| Manual Transmission problems | |
| Clutch problems | |
| Automatic Transmission problems | |
| Clutch Pedal/linkage problems | |
| Transmission Failure problems |