Mercedes-Benz has put all of its latest safety features into the CLS. In addition to front airbags, there are side-impact airbags in the front seats and side curtain airbags throughout. The car features a "smart" sensor system for the seatbelts and airbags that can detect and react to accident severity. An optional Pre-Safe system predicts an impending collision; when the system is activated, the seatbelts tighten, the front passenger seat adjusts to crash positioning, and the sunroof closes automatically.

The air suspension has three settings. The default setting, "Comfort," is ideal under normal driving conditions, stiffening as the car's speed increases. "Sport 1" and "Sport 2" settings give the car more agility on winding and bumpy roads. The car can also be raised three inches (76 mm) ,

The engine displacement is increased to 6.3 litres (producing 720 hp (540 kW)) and the suspension, brakes and transmission are optimized.