The third and final generation of the CL-Class (C216) premiered in late 2006 on the S-Class W221 platform. The C216 combined flared wheel arches and a bold front grille with classic pillarless hardtop elegance. Advanced safety innovations premiered on the C216 included Night View Assist with infrared imaging, PRE-SAFE Brake autonomous braking, and active lane-keeping systems. The hydraulic Active Body Control (ABC) system gained Crosswind Stabilization in 2009.

Powertrains initially comprised the naturally aspirated 5.5-liter V8 in the CL 500 and the 5.5-liter twin-turbo V12 in the CL 600. AMG offered the CL 63 AMG (naturally aspirated 6.2L V8, later replaced by a 5.5L biturbo V8) and the formidable CL 65 AMG (6.0L biturbo V12 with up to 630 hp). A major 2010 mid-cycle update introduced a direct-injected 4.7-liter V8 biturbo (435 hp) for the CL 500 alongside optional 4MATIC all-wheel drive. In 2014, the CL designation was retired as Mercedes reunited its grand touring coupes under the S-Class Coupe badge.