Derived from a coupe study that appeared at the 2003 Frankfurt Motor Show in Germany, the four-door CLS-Class features a high belt line and short side glass. A distinctive body crease rises from the front wheel arch, extends across the bodyside and continues through the contoured rear light cluster into the back bumper. The roofline forms a sweeping arc above the body before smoothly transitioning into the C-pillar, which appears pulled toward the rear of the car. Aluminum is used for the front and rear subframes, parcel shelf and other components. Aerodynamically speaking, the car has a coefficient of drag of 0.30.

Built on a 112.4-inch wheelbase, the CLS-Class is slightly more than 193 inches long overall and nearly 74 inches wide.

Alloy wheels hold 18-inch tires on the CLS500, but the CLS55 AMG gets 19-inchers. Projector-type headlights are standard, and bi-xenon headlights are optional. An automatic cornering light function with the bi-xenon units switches on the cornering lights during a turn, and the adaptive headlights pivot to follow the driver's steering movements.